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The dataset generation failed because of a cast error
Error code: DatasetGenerationCastError
Exception: DatasetGenerationCastError
Message: An error occurred while generating the dataset
All the data files must have the same columns, but at some point there are 15 new columns ({'summary', 'pub_date', 'comments', 'hgnc_gene', 'summary_comments', 'entry_index', 'mondo_id', 'assertion', 'evidence_code', 'mode_inheritance', 'disease', 'path', 'expert_panel', 'variant', 'met_status'}) and 9 missing columns ({'Reason for Changed Score', 'Score Status', 'Points (default points)', 'Explanation', 'url', 'Experimental Category', 'primary_index', 'Reference', 'Label'}).
This happened while the csv dataset builder was generating data using
hf://datasets/owencqueen/cgbench_data/VCI/split_evidence_score/train.csv (at revision 34fd1179dc7eda9709d682704d00935c0dccac67)
Please either edit the data files to have matching columns, or separate them into different configurations (see docs at https://hf.co/docs/hub/datasets-manual-configuration#multiple-configurations)
Traceback: Traceback (most recent call last):
File "/src/services/worker/.venv/lib/python3.9/site-packages/datasets/builder.py", line 1871, in _prepare_split_single
writer.write_table(table)
File "/src/services/worker/.venv/lib/python3.9/site-packages/datasets/arrow_writer.py", line 643, in write_table
pa_table = table_cast(pa_table, self._schema)
File "/src/services/worker/.venv/lib/python3.9/site-packages/datasets/table.py", line 2293, in table_cast
return cast_table_to_schema(table, schema)
File "/src/services/worker/.venv/lib/python3.9/site-packages/datasets/table.py", line 2241, in cast_table_to_schema
raise CastError(
datasets.table.CastError: Couldn't cast
entry_index: int64
variant: string
hgnc_gene: string
disease: string
mondo_id: string
assertion: string
mode_inheritance: string
expert_panel: string
pub_date: string
evidence_code: string
met_status: string
pmid: string
comments: string
summary: string
summary_comments: string
path: string
-- schema metadata --
pandas: '{"index_columns": [{"kind": "range", "name": null, "start": 0, "' + 2155
to
{'Label': Value(dtype='string', id=None), 'Experimental Category': Value(dtype='string', id=None), 'Reference': Value(dtype='string', id=None), 'Explanation': Value(dtype='string', id=None), 'Score Status': Value(dtype='string', id=None), 'Points (default points)': Value(dtype='string', id=None), 'Reason for Changed Score': Value(dtype='string', id=None), 'url': Value(dtype='string', id=None), 'primary_index': Value(dtype='int64', id=None), 'pmid': Value(dtype='string', id=None)}
because column names don't match
During handling of the above exception, another exception occurred:
Traceback (most recent call last):
File "/src/services/worker/src/worker/job_runners/config/parquet_and_info.py", line 1433, in compute_config_parquet_and_info_response
parquet_operations = convert_to_parquet(builder)
File "/src/services/worker/src/worker/job_runners/config/parquet_and_info.py", line 1050, in convert_to_parquet
builder.download_and_prepare(
File "/src/services/worker/.venv/lib/python3.9/site-packages/datasets/builder.py", line 925, in download_and_prepare
self._download_and_prepare(
File "/src/services/worker/.venv/lib/python3.9/site-packages/datasets/builder.py", line 1001, in _download_and_prepare
self._prepare_split(split_generator, **prepare_split_kwargs)
File "/src/services/worker/.venv/lib/python3.9/site-packages/datasets/builder.py", line 1742, in _prepare_split
for job_id, done, content in self._prepare_split_single(
File "/src/services/worker/.venv/lib/python3.9/site-packages/datasets/builder.py", line 1873, in _prepare_split_single
raise DatasetGenerationCastError.from_cast_error(
datasets.exceptions.DatasetGenerationCastError: An error occurred while generating the dataset
All the data files must have the same columns, but at some point there are 15 new columns ({'summary', 'pub_date', 'comments', 'hgnc_gene', 'summary_comments', 'entry_index', 'mondo_id', 'assertion', 'evidence_code', 'mode_inheritance', 'disease', 'path', 'expert_panel', 'variant', 'met_status'}) and 9 missing columns ({'Reason for Changed Score', 'Score Status', 'Points (default points)', 'Explanation', 'url', 'Experimental Category', 'primary_index', 'Reference', 'Label'}).
This happened while the csv dataset builder was generating data using
hf://datasets/owencqueen/cgbench_data/VCI/split_evidence_score/train.csv (at revision 34fd1179dc7eda9709d682704d00935c0dccac67)
Please either edit the data files to have matching columns, or separate them into different configurations (see docs at https://hf.co/docs/hub/datasets-manual-configuration#multiple-configurations)Need help to make the dataset viewer work? Make sure to review how to configure the dataset viewer, and open a discussion for direct support.
Label
string | Experimental Category
string | Reference
string | Explanation
string | Score Status
string | Points (default points)
string | Reason for Changed Score
string | url
string | primary_index
int64 | pmid
string |
|---|---|---|---|---|---|---|---|---|---|
Yoshimura_Expression
|
Expression A
|
Yoshimura H, et al., 2014, PMID: 24676347
|
Investigation of differential expression of many genes in the mouse cochlea between apical, middle, and basal turns revealed that CRYM expression was higher in the apex than in the base.
|
Score
|
0.25 (0.5)
|
0.25 points given because no explanation of relevance to CRYM hearing loss is provided
|
https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_d15cf48a-3696-467a-b3c8-a45ef5a577bf-2021-09-21T160000.000Z
| 534 |
PubMed:24676347
|
Northern and Western Blot
|
Expression A
|
Faulkner G, et al., 1999, PMID: 10427098
|
Northern blot analysis revealed LDB3 is expressed in the heart and skeletal muscle. Western blot analysis was also consistent with this finding.
|
Score
|
0.5 (0.5)
| null |
https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_7756e3c0-5a16-49b8-ac0f-220e79a4fa99-2020-09-25T160000.000Z
| 1,194 |
PubMed:10427098
|
crystal structure of BMP9:ALK1 complex at 3.3 Å
|
Protein Interaction
|
Salmon RM, et al., 2020, PMID: 32238803
|
ALk1 variants have been found in a number of probands with hereditary hemorrhagic telangiectasia. ALK1-mediated endothelial BMP9 and BMP10 signaling plays many important roles in angiogenesis and the maintenance of vascular quiescence. This paper demonstrated that the BMP9 GF-domain binds to the extra cellular domain of ALK1 with minimal conformational change. The entire ALK1 complex with pro-BMP9 is shown in figure 6.
|
Score
|
0.5 (0.5)
| null |
https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_00608fb7-3483-495a-8f9e-76aabb4b1dc0-2023-04-03T160000.000Z
| 879 |
PubMed:32238803
|
Taok1 knock-down embryonic mouse brain
|
Model Systems Non-human model organism
|
van Woerden GM, et al., 2021, PMID: 33565190
|
Reduced Taok1 expression levels in the embryonic mouse brain affect neural migration in vivo, a process that is critical for normal brain development.
|
Score
|
1.5 (2)
|
Because TAOK1 role in neuronal migration was scored in other experimental evidences included in this curation, evidence from this model system was lowered to prevent scoring the same evidence twice.
|
https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_79c712d0-ac0e-4bf0-8e68-bd598b3bca42-2021-08-04T160000.000Z
| 2,130 |
PubMed:33565190
|
COL6A1 Spontaneous Canine Model
|
Model Systems Non-human model organism
|
Steffen F, et al., 2015, PMID: 26438297
|
This naturally occurring model of Collagen VI-related myopathy is remarkably similar to the severe spectrum of disorder observed in human, the canines recapitulate the most important phenotypes observed in humans such as progressive muscle weakness, contractures, non-ambulation, and the muscular signs on biopsy including fiber size variation and degeneration, necrosis, and endomysial tissue infiltration into the muscle fibers.
|
Score
|
2 (2)
| null |
https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_9de84294-8404-4bd0-a7c6-89a9a70eb408-2022-09-26T160000.000Z
| 487 |
PubMed:26438297
|
Chen_Rescue Mouse
|
Rescue Non-human model organism
|
Chen JC, et al., 2020, PMID: 31481471
|
Using this method, authors showed that the enzyme gets precisely delivered to acidified lysosomes, where it exists as a stable dimer and results in substrate clearance in the brain tissue of affected mice. Authors suggest that once the uptake capacity of lysosomes was saturated, the remaining extracellular enzyme was likely cleared. rhbeta-gal activity levels in liver and bone marrow of ERT–treated KO mice were normalized, suggesting systemic exposure to the enzyme.
|
Score
|
2 (2)
|
Default points are scored.
|
https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_0019c7ef-4e2f-4f32-ab42-decfa0b20c29-2023-04-28T160000.000Z
| 900 |
PubMed:31481471
|
V1316M Knock-in Mice
|
Model Systems Non-human model organism
|
Adam F, et al., 2016, PMID: 27212476
|
Homozygous KI-mice replicated human VWD-type 2B with macrothrombocytopenia (platelet counts reduced from 1019x10^3 to 455x10^3/uL, platelet volume increased by 44%), circulating platelet aggregates, reduced high molecular weight multimers, and a severe bleeding tendency with all mice failing to stop bleeding in a tail clip-bleeding assay. Heterozygous mice also had a modest, but significant reduction in platelet count (914x10^3/uL) and 6% increase in platelet volume, as well as presence of platelet aggregates, reduction of high molecular weight multimers, and a heterogeneous bleeding phenotype with either prolonged bleeding of failure to stop bleeding.
|
Score
|
3 (2)
|
The V1316M, initially identified in humans, was knocked in to mice, which display a distinct VWD-type 2B phenotype, severe for the homozygous KI-mice and more moderate for the HET-mice. In humans, VWD-type 2B is of dominant inheritance and is usually present in a heterozygous state. In the murine model, although HET-mice do display some features of the disease, only homozygous-KI-mice fully phenocopy the human clinical picture.
|
https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_ecfe8bc1-5a4b-4d41-80d1-217af5b5b77f-2020-09-23T160000.000Z
| 2,332 |
PubMed:27212476
|
RNA expression in human cadaver eyes
|
Expression A
|
Zhang T, et al., 2021, PMID: 33553197
|
RNA expression analysis in human cadaver eyes confirmed wide expression of SNRNP200 in multiple eye tissues including cornea, iris, lens, vitreous body, sclera, retina, and optic nerve.
|
Score
|
0.5 (0.5)
| null |
https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_41acb15c-18a0-412b-a308-66a7f4e2837a-2022-05-24T160000.000Z
| 2,061 |
PubMed:33553197
|
Murine model
|
Model Systems Non-human model organism
|
Gomes J, et al., 2012, PMID: 22240500
|
ARVC patients carrying heterozygous DSP mutations experienced unexplained syncope, ventricular tachycardia or ventricular fibrillation. Isochronal mapping identified a clearly prolonged reight ventricular depolarization (outflow tract) in these patients. Immunohistochemistry from biopsies from DSP-ARVC patients revealed mislocalization of Cx43.
DSP± mice had normal ECG but delayed conduction and inducible ventricular tachycardia associated with mislocalization and reduced intercalated disc expression of Cx43. Histological studies of DSP heterozygous KO mice showed focal myocyte loss and fibro-fatty replacement
|
Score
|
2 (2)
| null |
https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_b23da580-269c-4e5d-8f13-91dbe7ea6a57-2019-07-12T160000.000Z
| 661 |
PubMed:22240500
|
Munis Cell Culture Rescue
|
Rescue Cell culture model
|
Munis AM, et al., 2021, PMID: 33426150
|
Following the rescue, immunoblotting showed SFTPB knockout cells with expression of mature SPB homodimer and transepithelial electrical resistance (TEER) levels increased to be comparable with wild type SALI cultures. Treatment with a control vector expressing EGFP failed to generate SPB homodimers and did not correct the TEER.
|
Score
|
0.5 (1)
|
Score reduced as cell culture model evidence from the same paper is scored.
|
https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_4bfa265f-3b7a-4091-8e97-b13a7f4f2de7-2024-10-17T190000.000Z
| 1,966 |
PubMed:33426150
|
K78R knock-in mouse model
|
Model Systems Non-human model organism
|
Colombo S, et al., 2023, PMID: 37275776
|
Variant-specific mouse model demonstrates features associated with developmental and motor delay (figure 1) and recapitulates a seizure phenotype that is often reported in individuals with GNB1-related neurodevelopmental disorders (figure 2). The seizure phenotype was demonstrated by EEG (figure 2) and further studied using P0 ex vivo cortical neurons (figure 3). The seizure phenotype of this mouse model was independently confirmed by a second group (PMID: 36405774).
|
Score
|
2 (2)
| null |
https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_f83c8548-99d7-489d-8582-ac4ad5abd0ec-2023-08-16T040000.000Z
| 2,939 |
PubMed:37275776
|
MYOC Mutations Activate Stress Pathway
|
Functional Alteration Non-patient cells
|
Itakura T, et al., 2015, PMID: 26396484
|
The wild-type MYOC protein was found entirely in the cell culture medium, while the mutant proteins were retained entirely in the cell according to western blot analysis. The activity of stress-response genes associated with glaucoma, such as IL1A, ACTA2, and FOXO1 were increased in these cells similarly to those found in glaucoma patients. This signals an increased stress on the cells, part of the mechanism of MYOC-related glaucoma. The expression of the variants also caused cellular toxicity, with cell death after long exposure. This is also observed in glaucoma patients, with premature apoptosis being a mechanism for the increased pressure. These results were further confirmed with the addition of a mild POAG variant; both the wild-type and A427T were found in the medium, with the mutants collecting in the cell lysates.
|
Score
|
0.5 (0.5)
|
This evidence shows that mutant MYOC accumulating influences the stress pathway, causing cell toxicity and apoptosis. It also upregulates stress genes seen in glaucoma patients. This evidence is enough to earn default points.
|
https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_fe5896cf-ec59-431e-bf95-02de61729269-2022-02-17T170000.000Z
| 1,448 |
PubMed:26396484
|
Peden_Rescue
|
Rescue Cell culture model
|
Peden AA, et al., 2002, PMID: 11807095
|
Cells expressing the wild-type Ap3d1 take up less anti–LAMP-1 than non-trandfected cells, indicating less misrouting of LAMP-1 to the plasma membrane in them.
|
Score
|
0.5 (1)
|
The evidence is awarded minimum points as the rescue pertains to a molecular aspect and not the disease phenotype.
|
https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_3ec9ffa2-efda-446d-a848-e6d4d5b92fb6-2023-06-07T160000.000Z
| 2,510 |
PubMed:11807095
|
Rescue experiment in Zebrafish model
|
Rescue Non-human model organism
|
Ramirez IB, et al., 2012, PMID: 22210625
|
Phenotype of brain size, apoptosis, and proliferation in OCRL deficient zebrafish embryos can be partially rescued by expression of wild type but not mutant OCRL
|
Score
|
1 (2)
|
Zebrafish cDNA, not human cDNA is used for rescue experiment
|
https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_5140c756-fac0-435b-8f59-a5d4a0b0adb3-2020-07-10T160000.000Z
| 1,582 |
PubMed:22210625
|
Redig knockout mouse
|
Model Systems Non-human model organism
|
Redig JK, et al., 2014, PMID: 25328912
|
Knock-out CRELD1 mice presented fewer cells and less extracellular matrices in the atrioventricular endocardial cushions than wild-type mice.
Creld1 knockout mouse model combined with increased VEGFA showed abnormal morphogenic response to VEGFA in Creld1-deficient embryonic hearts, indicating that interaction between CRELD1 and VEGFA has the potential to alter atrioventricular canal morphogenesis
Complete knockout of Creld1 resulted in embryonic lethality, while heterozygotes were phenotypically normal but displays biochemical abnormalities that predispose the developing heart to an aberrant response to increased VEGFA signaling.
CRELD1 plays a role in regulating VEGFA and that CRELD1 haploinsufficiency alone causes dysregulation of VEGFA
|
Score
|
1 (2)
|
Genotype does not match human patients
|
https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_1aa67af6-c8df-4151-98ab-049b69fefd08-2023-09-05T160000.000Z
| 529 |
PubMed:25328912
|
In situ hybridization of PRPS1a and b in zebrafish inner ear
|
Expression A
|
Pei W, et al., 2016, PMID: 27425195
|
In situ hybridization of PRPS1a and PRPS1b in zebrafish was found to be relatively enriched in the inner ear, embryonic brain and caudal hematopoiteic tissue.
|
Score
|
0.5 (0.5)
| null |
https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_9416f6e2-8de3-48b0-9a1c-9bd11a59315c-2020-02-14T170000.000Z
| 1,769 |
PubMed:27425195
|
Col6A2 KO mouse
|
Model Systems Non-human model organism
|
Meehan TF, et al., 2017, PMID: 28650483
|
Mice displayed decreased grip strength consistent with the muscle weakness observed in patients.
|
Score
|
0.25 (2)
|
Col6A KO mice were not well described, only a decreased grip strength was noted as such full recapitulation of human disease cannot be confirmed. Additionally, the mechanism of disease here (homozygous knockout) does not match the dominant negative mechanism being evaluated in this curation.
|
https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_a7a4dad5-f179-44ac-adcb-c5e15c11a1ec-2022-06-27T160000.000Z
| 488 |
PubMed:28650483
|
Byun et al. Rescue in patient cells
|
Rescue Patient cells
|
Byun M, et al., 2013, PMID: 23897980
|
Despite expressing low levels of OX40 on the cell surface, the patient had completely abolished OX40 ligand binding on PHA activated T cells. Lentiviral transfection of OX40-WT rescued this phenotype, restoring OX40 ligand binding in patient T cells. Meanwhile, lentiviral transfection of the patient variant OX40-R65C, failed to rescue this phenotype. This result is also in line with severely impaired OX40 ligand binding in Jurkat cells expressing the OX40-R65C variant.
|
Score
|
1 (1)
| null |
https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_4759ec3f-6876-41c4-a6eb-fdceedccbc60-2023-06-15T170000.000Z
| 2,205 |
PubMed:23897980
|
Rela+/− mice
|
Model Systems Non-human model organism
|
Badran YR, et al., 2017, PMID: 28600438
|
TNF stimulation of Rela+/− splenocytes resulted in significantly impaired up-regulation of Il6, Tnfaip3, and Traf1; all which depend on NF-κB activation. A low-dose, s.c. TNF injection had no effect on WT mice but resulted in cutaneous ulceration in Rela+/− mice, which was notable for epidermal skin loss and a predominance of neutrophils and macrophages in the dermis and hypodermis. This is consistent with the cutaneous (oral and genital) ulcers observed in patients.
|
Score
|
2 (2)
| null |
https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_1e0145f5-c001-420c-9591-c6583862a7ca-2023-09-21T160000.000Z
| 1,842 |
PubMed:28600438
|
C. elegans CMTX6 knock-in model
|
Model Systems Non-human model organism
|
Narayanan RK, et al., 2021, PMID: 34387338
|
The C. elegans models generated in this study recapitulate various molecular phenotypes observed in both the CMTX6 fibroblasts and iPSC-derived motor neurons, and motor phenotypes observed in patients.
|
Score
|
2 (2)
| null |
https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_508a1db7-0cf1-4c28-9203-89a3f4d7438d-2024-03-14T160000.000Z
| 1,640 |
PubMed:34387338
|
Biochemical function 1
|
Biochemical Function A
|
Stessman HA, et al., 2017, PMID: 28191889
|
KMT5B as one of a group of epigenetic modifier genes that are critical for typical neurodevelopment, such as EHMT1 and ARID1B, which are associated with Kleefstra syndrome (OMIM: 610253) and Coffin-Siris syndrome (OMIM: 135900). KMT enzymes (KMT5A, B, anc C) play an epigenetic role by acting as histone methyltransferases and 'writing' H4K20 methylation marks. Another gene family of H4K20 writers, the NSD family, are also associated with neurodevelopmental disorders (NDD): NSD1: Sotos syndrome andNSD2: Wolf-Hirschhorn syndrome. De novo variants have also been identified among individuals with NDD for many of the other writers, erasers and readers of the H4K20 mark (Table S1, which includes cited PMIDs to support the associations).
|
Score
|
0.5 (0.5)
|
Shares a function with other genes associated with neurodevelopmental disorders.
|
https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_885d56b0-a2b0-4a3d-9f11-4034298e074e-2022-04-08T072351.945Z
| 1,177 |
PubMed:28191889
|
siRNA mediated CDT1 knockdown in control fibroblasts
|
Functional Alteration Non-patient cells
|
Stiff T, et al., 2013, PMID: 23516378
|
impaired BrDU incorporation, impaired cilia formation, increased centrosome number, and aberrant chondroinduction phenotype. Similar alterations have been observed in ORC1-deficient patient cells, another gene implicated in pathogenesis of MGS
|
Score
|
0.5 (0.5)
| null |
https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_dfc9602f-fb88-419a-8955-6d7c00a52158-2023-03-03T170000.000Z
| 366 |
PubMed:23516378
|
Conditional mouse knockdown
|
Model Systems Non-human model organism
|
Cabello-Rivera D, et al., 2019, PMID: 31297047
|
Ndufs2 flox/– alleles and the hGFAP-Cre transgene (hGFAP-NDUFS2 mice)
postnatal day (P) 0 hGFAP-NDUFS2 mice were apparently indistinguishable from littermates and their brains were macroscopically similar to controls (Figure 1A), the histological analyses revealed a decrease in cortical thickness (Figure 1B) and subtle hippocampal abnormalities (Figure 1C).
At P5, hGFAP-NDUFS2 mice showed a rapid decline, showing decreased body size and onset of ataxia, and died between P7 and P9.
Brain abnormalities included abnormal dorsal cortical areas, the hippocampus and cerebellum (Figures 2B–F). Ndufs2 knockout mice displayed ventricle dilatation and corpus callosum atrophy
(Figure 2B). MCI activity was markedly reduced in cells of the dorsal telencephalon from hGFAP-NDUFS2 mice (Figure 2H)
|
Score
|
2 (2)
|
Reduction MCI, reduction in ATP synthesis, Phenotype: regression and ataxia
|
https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_6df726c1-2897-46f8-aed1-f9939b9acf0c-2021-04-09T143144.546Z
| 1,499 |
PubMed:31297047
|
Overexpression rescue the cell KO phenotype
|
Rescue Cell culture model
|
Minaidou A, et al., 2018, PMID: 29845787
|
growth recovery with formation of early neurites. Patient variant failed to rescue the phenotype
|
Score
|
1 (1)
| null |
https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_82dac4c0-801f-4704-b59d-0a9441423d5a-2023-11-28T170000.000Z
| 1,230 |
PubMed:29845787
|
RC phosphorylation
|
Biochemical Function B
|
Muthu P, et al., 2012, PMID: 21696541
|
Show that MLCK (MYLK2) can phosphorylate RLC (MLC2/MYL2) and modulate myofibrillar ATPase activity. Looking at the WT OE transgenic human ventricular mysoin RLC mouse and tissue.
|
Score
|
0.5 (0.5)
| null |
https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_6f0f41e3-7b5b-477c-b45d-598b5f8f3df0-2023-02-08T170000.000Z
| 2,600 |
PubMed:21696541
|
Complex II structure
|
Biochemical Function A
|
Fullerton M, et al., 2020, PMID: 33162331
|
Pathogenic variants in these genes are associated with Leigh syndrome:
SDHA- GDR is moderate by ClinGen SOP v6
SDHB- GDR is moderate by ClinGen SOP v8
SDHD -
SDHAF1-GDR is limited by ClinGen SOP v7
|
Score
|
0 (0.5)
|
Not scored at this time due to lack of genetic evidence. Can be scored upon availability of genetic evidence.
|
https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_909982e0-a53c-4a87-bf28-cdb563c8ae62-2022-03-07T170000.000Z
| 1,940 |
PubMed:33162331
|
Rescue of siRNA treated cells
|
Rescue Cell culture model
|
Brooks SP, et al., 2010, PMID: 20332100
|
Re-expression of the NHS-1A isoform reduced the cell surface area, similar to control/WT cells. Also, the lamellapodia phenotype was ameliorated upon re-expression of NHS-1A.
|
Score
|
1 (1)
| null |
https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_a7f57ca3-efb2-4333-9ae1-732aa429f37a-2017-10-20T040000.000Z
| 1,539 |
PubMed:20332100
|
POMGNT2 knockout in HAP1 cells
|
Functional Alteration Non-patient cells
|
Endo Y, et al., 2015, PMID: 27066570
|
HAP1 POMGNT2 knockout cells exhibited defects in their reactivity to the anti-α-dystroglycan antibody IIH6, which detects the glycosylated form of α-dystroglycan, when observed by fluorescent microscopy. Furthermore, no glycosylated α-dystroglycan was visible in western blot of protein from HAP1 POMGNT2 knockout cells.
|
Score
|
1 (0.5)
|
The score for this functional alteration evidence was upgraded to 1 point from a default of 0.5 points given the ability of the wild type POMGNT2 cDNA to rescue the α-dystroglycan glycosylation defects in HAP1 POMGNT2 knockout cells.
|
https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_522f3d3f-8026-439f-9318-2e4df6097a2e-2024-08-14T190000.000Z
| 2,853 |
PubMed:27066570
|
Ubtf E210K expression in mouse fibroblasts
|
Functional Alteration Non-patient cells
|
Tremblay MG, et al., 2022, PMID: 35139074
|
Ubtf E210K/E210K mouse embryonic fibroblasts had >40% lower rate of pre-rRNA synthesis, >40% less RNA polymerase I loading across the rDNA, reduced SL1 (another transcription factor for RNA polymerase I) and UBTF recruitment to the rDNA promoter, and 30% less total cellular RNA. Unexpectedly, the Ubtf E210K mouse fibroblasts also showed a significant increase in the fraction of activated rDNA copies leading to an increased expression of UBTF1 (at both the transcript and protein levels). The authors proposed that the underlying cause of the UBTF-E210K syndrome is a reduction in cooperative UBTF1-SL1 promoter recruitment that may be partially compensated by enhanced rDNA activation.
|
Score
|
0.25 (0.5)
|
These experiments were performed in fibroblasts from embryonic mice homozygous for the E210K variant whereas patients are heterozygous.
|
https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_1a5d6060-b955-49a0-9804-265838495310-2023-08-16T190000.000Z
| 2,296 |
PubMed:35139074
|
Restoration of peroxisome morphology
|
Rescue Patient cells
|
Costello JL, et al., 2017, PMID: 28108524
|
Reintroduction of MFF resulted in formation of numerous spherical peroxisomes, restoring the normal phenotype
|
Score
|
1 (1)
| null |
https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_021d15d7-dbf0-4b71-bbb5-48dc4a4b5ee6-2024-06-21T160000.000Z
| 2,815 |
PubMed:28108524
|
Yeast two hybrid analysis: ODA16 and IFT46
|
Protein Interaction
|
Ahmed NT, et al., 2008, PMID: 18852297
|
ODAs are actively transported into cilia via the intraflagellar transport (IFT) system and the transport adaptor ODA16. IFT46 is a core component of the intraflagellar transport machinery and is required for the formation of all cilia. Knockdown of IFT46 causes shortening of the body axis as well as the formation of fewer and shorter cilia (PMID: 33628615). IFT46 knockout mice exhibit defects in left–right axis patterning (including heart defects) and short cilia (PMIDs: 25722189, 27320864). IFT46 and ODA16 are thought to interact to transport ODAs via the IFT.
|
Score
|
0.5 (0.5)
| null |
https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_999c6072-d9c6-4339-aea7-8247941748a6-2024-07-11T160000.000Z
| 575 |
PubMed:18852297
|
BCL11A structural and behavioral abnormalities in mice
|
Model Systems Non-human model organism
|
Dias C, et al., 2016, PMID: 27453576
|
Mouse model showed alterations in cognition and brain morphology similar to that described in Dias-Logan syndrome patients. Using a number of different behavioral paradigms, Bcl11a haploinsufficient mice were found to have impaired cognition, abnormal social behavior, and microcephaly, in line with intellectual disability, autistic features, and microcephaly observed in human cases.
Note that the authors also used HEK293 cell to confirm the pathogenicity of the three missense variants observed (Subjects 1-3).
|
Score
|
2 (2)
| null |
https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_9630f9a3-3f90-49c6-ae8b-6313c950b1b2-2020-09-13T171807.228Z
| 220 |
PubMed:27453576
|
Panda Mouse Model
|
Model Systems Non-human model organism
|
Panda SP, et al., 2013, PMID: 24086598
|
The aberrant development of the skull upon POR deletion in osteoprogenitor cells in this mouse model not only implicates POR in bone development but it recapitulates, at least partially, the observed craniofacial deformities and bone defects leading to fracture in severe POR-deficient human patients
|
Score
|
2 (2)
| null |
https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_6275d46a-f005-45f8-b3ec-e9722f8dd39e-2022-03-23T193729.312Z
| 1,733 |
PubMed:24086598
|
UROC1 in Histidine Metabolism
|
Biochemical Function B
|
Glinton KE, et al., 2019, PMID: 30619714
|
Defects in this section of histidine metabolism would certainly cause the biochemical abnormality characteristic of this disorder, urocanic aciduria, due to the buildup of the metabolite directly before this step in the pathway.
|
Score
|
2 (0.5)
|
As the function of urocanase in histidine metabolism is very well-characterized, and the biochemical abnormality characteristic of the disorder is a direct result of the loss-of-function in this enzyme, this evidence scores maximum points.
|
https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_af2ff293-39ce-46b7-af58-01e3685f4334-2024-04-26T160000.000Z
| 2,926 |
PubMed:30619714
|
Zebrafish null
|
Model Systems Non-human model organism
|
Albers CA, et al., 2011, PMID: 21765411
|
The model system recapitulates human phenotypes of thrombocytopenia and abnormal bleeding, manifested as spontaneous bleeding the the tail of the MO-zebrafish.
|
Score
|
1 (2)
|
The zebrafish recapitulated human phenotypes but was more severe, which may be expected due to the difference between a null-phenotype in zebrafish and a loss of function one in the GPS cases. Also the typical GPS platelet morphology (i.e.absent alpha-granules) was not observed due to the complete abrogation of thrombocytes in the zebrafish.
|
https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_ae8bd4d6-8810-423b-83e0-98667f06426d-2019-06-26T160000.000Z
| 1,464 |
PubMed:21765411
|
STAT3 DNA binding
|
Functional Alteration Non-patient cells
|
Asano T, et al., 2021, PMID: 34137790
|
Transfection of variants into HEK293 cells resulted in the reduction of STAT3 DNA binding for the majority of variants. For those variants without decreased DNA binding, alternative splicing was investigated, and it was found that alternative transcripts or translation reinitiating were being generated that resulted in variants with dominant negative effects.
|
Score
|
1 (0.5)
|
This is an extensive work that demonstrates the vast majority of STAT3 LOF variants are dominant negative and not loss of heterozygosity. I have upgraded the score due to the vast number of variants tested, as well as the quality of the data generated.
|
https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_beb3aa5b-240e-45d7-969a-9de3e5564457-2021-12-24T160548.234Z
| 2,104 |
PubMed:34137790
|
Mouse model
|
Model Systems Non-human model organism
|
Alharatani R, et al., 2020, PMID: 32196547
|
The cleft palate and brain structural anomalies seen in the mice reflect anomalies seen in affected humans.
|
Score
|
1 (2)
|
The heterozygous mutants had no cleft lip/palate, or facial/arm/leg anomalies, so the score is downgraded.
|
https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_5000144a-71c1-4ae7-95a9-17ad67a388c5-2024-03-21T160000.000Z
| 552 |
PubMed:32196547
|
Neulen 2009 FunctAlt1
|
Functional Alteration Non-patient cells
|
Neulen A, et al., 2009, PMID: 19506933
|
Effect of L29Q on isometric force and unloaded shortening velocity in triton-skinned myocardium. Results showed no statistical significance.
|
Score
|
0 (0.5)
|
Triton-skinned myocardium preparations have no functional cell membranes or sarcoplasmic reticulum, but myofilamint lattice is intact.
|
https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_5d832673-8acb-4a02-ae34-35e0d9981b70-2023-09-13T160000.000Z
| 2,208 |
PubMed:19506933
|
Omran et al. 2008 Chlamydomonas
|
Model Systems Non-human model organism
|
Omran H, et al., 2008, PMID: 19052621
|
One of the recurring phenotypes of PCD in human patients is ODA and IDA defects. This experiment with Chlamydomonas demonstrates loss of motility (paralyzed flagella) as well as recurrence of the partial ODA and IDA loss.
|
Score
|
1 (2)
|
Downscored due to the model being unable to display the respiratory phenotypes like humans
|
https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_39e5de96-3f16-4dde-a7bc-b3e27364b7f8-2024-02-08T170000.000Z
| 615 |
PubMed:19052621
|
TECRLc.331+1G>A characterisation
|
Functional Alteration Patient cells
|
Devalla HD, et al., 2016, PMID: 27861123
|
Analysis of intracellular calcium ([Ca2+]i) dynamics revealed smaller [Ca2+]i transient amplitudes as well as elevated diastolic [Ca2+]i in TECRL-homozygous-hiPSC-CMs with the TECRLc.331+1G>A mutation compared with Control-hiPSC-CMs. The [Ca2+]i transient also rose markedly slower and contained lower sarcoplasmic reticulum (SR) calcium stores, evidenced by the decreased magnitude of caffeine-induced [Ca2+]i transients.
TECRL-homozygous-hiPSC-CMs with the TECRLc.331+1G>A mutation showed prolonged action potentials (APs) compared with Control-hiPSC-CMs. Moreover, stimulation by noradrenaline significantly increased the propensity for triggered activity based on delayed afterdepolarizations (DADs).
|
Score
|
2 (1)
|
In-depth characterisation of variant effect with numerous assays and multiple effects demonstrated.
|
https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_6889dc44-eef0-4a4d-8fdb-aef2dc570f29-2021-01-20T170000.000Z
| 2,161 |
PubMed:27861123
|
Li Protein Interaction
|
Protein Interaction
|
Li D, et al., 2013, PMID: 23325789
|
Many binding partners of DIAPH1 were identified, including ACTB and ACTG1, several tubulins, and OSBPL2, a moderate hearing loss gene
|
Score
|
0.5 (0.5)
|
No connection made to hearing loss, but supports role in regulation of microfilament/microtubule function, which are important in hair cells. Downgraded to 0.25, however scoring for this model is combined with Carreira 2003 study to equal 0.5 points.
|
https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_43c017fd-ce70-4fbe-ad30-90f216adaa7d-2018-01-05T170000.000Z
| 598 |
PubMed:23325789
|
Misato Drosophila
|
Model Systems Non-human model organism
|
Min S, et al., 2017, PMID: 29255146
|
In this study, we have shown that depletion of mst in the whole muscle tissues specifically impaired intestinalfunctions while skeletal muscles remained unaffected.
Having shown that depletion of mst in the Drosophila visceral muscle elicits a series of intestinal phenotypes, we wondered whether genetic restoration of mst expression in mef2 > mst RNAi flies would rescue the phenotypes. By combining UAS-mst transgene with mef2 > mst RNAi flies, we observed that the dilated intestine of mef2 > mst RNAi flies was completely normalized by the restoration of mst expression in the flies
|
Score
|
0.5 (2)
|
Scored 0.5 points because of imperfect phenotype overlap - (visceral myopathy v. skeletal myopathy, some evidence for visceral myopathy as well)
|
https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_10089a58-c9b4-497a-afb0-d249220eb2aa-2023-05-18T160000.000Z
| 1,341 |
PubMed:29255146
|
mitophagy defects in dopaminergic parkin mutant patient neur
|
Functional Alteration Patient cells
|
Schwartzentruber A, et al., 2020, PMID: 32968089
|
There was significant cell death occurring throughout differentiation specifically in the PRKN mutant patient derived DA neurons; the percentage of cells surviving until the end of the differentiation was significantly reduced (mean ± SD, controls 83.62 ± 4.8; parkin mutants 52.72 ± 11.98)
We observe the same mitochondrial fragmentation at the end stage
of differentiation accompanied by an increase in mitochondrial number (Fig. 3A mitochondrial interconnectivity: controls 0.07 ± 0.003; PRKN mutants 0.04 ± 0.005 p < 0.05; Fig. 3B mitochondrial number (% normalised to controls): controls 100 ± 3.4; PRKN mutants 204 ± 35; p < 0.0001).
|
Score
|
1 (1)
| null |
https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_6b39c4a0-f6bd-4afc-b2a7-f234eab5a667-2023-01-18T190000.000Z
| 1,759 |
PubMed:32968089
|
MEF2C Neocortical and hippocampal KO mice
|
Model Systems Non-human model organism
|
Harrington AJ, et al., 2016, PMID: 27779093
|
The homozygous MEF2C floxed, Emx1-Cre mice (Mef2c cKO) were tested for a number of behavioral paradigms associated with learning and memory, and social interaction. Ultrasonic vocalization (USVs) were recorded in Mef2c cKO mice versus control littermates. The Mef2c cKO adult male mice prodiced 70% fewer USV calls in the presence of a sexually-receptive female than control littermates (Figure 5B). furthermore, the type of USC being produced by the Mef2C cKO mice varied significantly compared to wildtype littermates. When infantile mice (postnatal day 4-10) were recorded for USV production, the Mef2c cKO mice produced fewwer USVs than control littermates (figure 5D), supporting reduction in communication which is consistent with the absence of speech and/or language impairment observed in humans with MEF2C variants.
In the three chamber assay to test for sociability, the Mef2c cKO equally preferred the chamber housing another mouse than the empty chamber similar to control mice, however the Mef2c cKO did spend significantly less time interacting with the mouse in the chamber compared to control mice (figure 5E). This deficits was shown to be independent of any deficit in olfaction (Figure 5F). Nest building was also tested, and the Mef2c cKO mice showed significantly less structured nest building than control littermates (figure 5G). The Mef2C cKO also showed deficits in the sucrose preference test, indicating difference in reward-related behavior.
Mef2c cKO mice showed an increase in repetitive jumping behavior, with a 3 fold increase in both novel and home cage setting compared to control littermates (Figure 6A). This was also true of repetitive fine motor movements (Figure 6B). Hyperactivity was noted in the novel open cage paradigm (Figure 6D).
Mef2C cKO mice also showed significant deficits in the fear conditioning assays (figure 7C-E), in which robust freezing behaviors were not observed following tone-shock pairing, unlike that observed in the control littermates.
Lastly, RNA-seq performed on the somatosensory cortex of Mef2c cKO mice showed significantly reduced expression of gene associated with autism including Ntng1, Nlgn1, Nrxn1, Nrxn3, Pcdh19, Shank2, Shank3, Pten, and Htr1b.
|
Score
|
3 (2)
|
This mouse model follows the molecular mechanism described in the humans with MEF2C variation (loss of function) and outlines several behavioral deficits that are consistent with learning and memory and social deficits. Furthermore, RNA-seq performed on specific brain regions in the knockout mice show reduction in the expression of genes associated with Autism and intellectual disability, therefore I am increasing the score.
|
https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_34354e8f-4343-4fba-82ba-e49579e504bb-2019-02-06T170000.000Z
| 1,277 |
PubMed:27779093
|
Xenopus Model
|
Model Systems Non-human model organism
|
Alharatani R, et al., 2020, PMID: 32196547
|
The fact that the mutants had small craniofacial cartilages and reduced survival falls in line with the craniofacial phenotype seen in humans. The abnormal heart looping seen in the mice falls in line with the ventricular and atrial septal defects seen in a few affected human probands.
|
Score
|
1 (2)
|
Downgrading as the phenotype is not super specific to the craniofacial features seen in humans.
|
https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_5000144a-71c1-4ae7-95a9-17ad67a388c5-2024-03-21T160000.000Z
| 552 |
PubMed:32196547
|
HEK transfection
|
Functional Alteration Non-patient cells
|
Gao J, et al., 2015, PMID: 26196677
|
WT MCM2-transfected cells had significantly fewer apoptotic cells after 48h than mutant MCM2-transfected culture, and both were significantly higher than the culture that lacked exogenous MCM2. These results support that MCM2 has pro-apoptotic activity. The same results were seen with Western blot of whole cell lysates, with the ratio of caspase3 to cleaved caspase3 used as a measure of apoptosis.
|
Score
|
0.5 (0.5)
| null |
https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_29172723-c896-4cbf-a20b-9921fc72547f-2020-04-21T190000.000Z
| 1,263 |
PubMed:26196677
|
Function
|
Biochemical Function B
|
Blackburn PR, et al., 2017, PMID: 28919799
|
Disruption of any subunit of the BCKAD complex leads to an increase and BCAAs, causing toxicity of tissues.
|
Score
|
1 (0.5)
|
Well-known disease mechanism. Review: MSUD is caused by decreased function of the BCKAD enzyme complex, which is composed of E1, E2 (encoded by DBT) and E3 subunits. The BCKAD complex is involved in the second step of catabolism of branched-chain amino acids (BCAAs), which are essential for life.
|
https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_cfd1ebde-e447-4877-977e-f5b9fe434adc-2018-10-30T160000.000Z
| 576 |
PubMed:28919799
|
KO Mouse
|
Model Systems Non-human model organism
|
Reinholt BM, et al., 2013, PMID: 23626854
|
Both the affected mice and humans biopsy revealed myopathic changes and fiber size variability.
|
Score
|
1 (2)
|
Showed that Stac3 is essential for development of functional skeletal muscle and viable mice. This knockout model had a phenotype more severe than that observed in humans, causing neonatal lethality.
|
https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_940572b9-6a5a-4de1-8ee1-6394f589515f-2020-04-25T160000.000Z
| 2,672 |
PubMed:23626854
|
Mdm4 TM/TM MEFs
|
Model Systems Cell culture model
|
Toufektchan E, et al., 2020, PMID: 32300648
|
MDM4 is a negative regulator of p53. This culture model demonstrated that loss of function of MDM4 results in an increased activity of p53 and short telomeres, features observed in humans with germ line mutations.
|
Score
|
1 (1)
| null |
https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_5c4e0701-22d0-4e73-bf76-a23e9472fe3d-2024-12-10T170000.000Z
| 2,969 |
PubMed:32300648
|
Le Coz_in vitro
|
Model Systems Cell culture model
|
Le Coz C, et al., 2021, PMID: 33951726
|
The authors demonstrate that biallelic PU.1 ETS expression is important for human B and myeloid cell development in vitro, similar to that seen in humans. Following the gene alteration to model PU.MA patient haematopoiesis (as described above), surviving myeloid (CD33+) or B cell precursors (CD19intIgM−, CD19hiIgM−, or CD19hiIgM+) did not possess SPI1 exon five (PEST domain) mutations of any kind despite very high initial editing efficiency at that genomic site. In-frame exon four edits that preserved the ETS were tolerated in B cell precursors, whereas ETS-altering frameshift edits of exon four were not.
|
Score
|
1 (1)
| null |
https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_76a93861-b7d3-4d08-8882-6a7a1456b51a-2024-12-12T170000.000Z
| 2,966 |
PubMed:33951726
|
Mutations in Hydin impair ciliary motility in mice
|
Model Systems Non-human model organism
|
Lechtreck KF, et al., 2008, PMID: 18250199
|
The paper provides evidence on lack of central pair projection and abnormal ciliary bending in HYDIN mutant mice. Both defects are observed in humans and are responsible for inefficient mucociliary clearance observed in PCD patients. Moreover, hy3/hy3 mice, situs abnormalities, as judged by the analysis of lung lobation as well as liver and stomach position in several dozen animals, were not observed which is also consistent with Ciliary dyskinesia, primary, 5(without situs inversus).
|
Score
|
3 (2)
|
The paper continued previous work by Davy and Robinson, 2003 where Two mutant alleles of Hydin (hy3 and OVE459) have been characterized with no transcripts have been detected. Both structural and functional defects in the brain and tracheal cells of HYDIN mutant mice. Phenotypes and (non phenotype) matches their human counterparts. PMID 23022101 explained the occurrence of hydrocephalus in HYDIN mutant mice by the fact that integrity of the cilia motility of ependymal cells is mandatory for maintaining patency of the aqueduct of Sylvii, which connects the third and fourth brain ventricles. Thus, disruption of ependymal flow regularly causes hydrocephalus in mice. In contrast, human PCD-affected individuals carry only an increased risk of developing hydrocephalus. Therefore, hydrocephalus in mice remains a supportive evidence of defective ciliary structure and/ or function.
|
https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_6c491ab7-496f-43b9-9bca-500901cb686d-2022-02-22T183411.247Z
| 1,031 |
PubMed:18250199
|
Purification of human cohesin complexes.
|
Protein Interaction
|
Sumara I, et al., 2000, PMID: 11076961
|
human cohesin complexes
|
Score
|
0.5 (0.5)
| null |
https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_c281f5fd-d868-4425-a7b4-8e39e3b2090e-2019-06-19T160000.000Z
| 2,666 |
PubMed:11076961
|
Complex II structure
|
Biochemical Function A
|
Fullerton M, et al., 2020, PMID: 33162331
|
All the above genes are structural components of complex II.
|
Score
|
1 (0.5)
|
1 point as per LSS GCEP rubric
|
https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_9010c629-a86c-4f55-a45b-212b7aabdb6f-2022-04-04T160000.000Z
| 1,941 |
PubMed:33162331
|
FA Nonpatient Cells
|
Functional Alteration Non-patient cells
|
Dhindsa RS, et al., 2015, PMID: 27066543
|
Expression of mutant proteins decrease endocytosis activity in dominant negative manner. The G359A variant showed disrupted higher-order DNM1 oligomerization. EM of mutation DNM1-transfected HeLa cells and DNM1 mutate mice showed vesicle defects indicating vesicle scission activity
|
Review
|
0.5 (0.5)
|
This is variant-level functional evidence. I have removed it from the experimental evidence total and instead applied it as supporting evidence for the individual with the G359A variant.
Expression of mutant proteins decrease endocytosis activity in dominant negative manner.
|
https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_31f598a3-7efd-4e43-83f3-587e98924260-2024-02-06T080000.000Z
| 2,748 |
PubMed:27066543
|
Deaf14 mouse
|
Model Systems Non-human model organism
|
Carpinelli MR, et al., 2014, PMID: 24682784
|
In humans, Canavan disease is a leukodystrophy characterized by spongiform encephalopathy of the brain, progressive intellectual impairment, motor deficit, and death in childhood. Additional clinical symptoms include hearing and visual impairment and seizures.
Deaf14 mice were generated by ethyl-nitrosonurea screen and have a nonsense variant, c.516T>A (p.Tyr172Ter) variant in Aspa, which results in lack of gene product, These mice had a reduced startle response, due to an abnormal auditory brainstem response. The brain of deaf14 mice was grossly abnormal, with widely distributed spongiform encephalopathy and extensive vacuolation (Fig. 5). They developed a Parkinson’s disease-like tremor (by 280 days of life), had a shorter latency to fall off a rotating rod than wild type mice, indicating impaired motor coordination. In the open-field test, deaf14 mice made more moves but covered less distance than wild-type mice, suggesting ataxia.
Similarities between the deaf14 mouse model and human patients with Canavan disease include: biallelic of function variants in the ASPA gene, spongiform encephalopathy and extensive vacuolation within the brain, hearing impairment, impaired motor coordination, ataxia, and shortened life span.
|
Score
|
3 (2)
|
The score is increased because the mice are homozygous for a loss of function variant, as is observed in human cases, and several key features of Canavan disease are present. The biochemical features, such as increased NAA, were not reported.
|
https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_66306eff-659f-4508-a41b-1820e47e0e1d-2020-10-08T161701.633Z
| 170 |
PubMed:24682784
|
Mouse in situ hybridization
|
Expression A
|
Mommersteeg MT, et al., 2015, PMID: 25691540
|
Mouse ISH at E16.5
|
Score
|
0 (0.5)
|
Already scored for this expression in another study
|
https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_a0d0c93c-abf7-4bf2-8b0f-e47cfce87656-2024-09-03T160000.000Z
| 1,876 |
PubMed:25691540
|
AP4E1 Knockout mouse
|
Model Systems Non-human model organism
|
De Pace R, et al., 2018, PMID: 29698489
|
Impaired motor coordination and weak grip strength seen in AP4E1 KO mice is consistent with impaired motor development, hypotonia and spastic paraplegia in humans
Thin corpus callosum found in AP4E1 KO mice is similar to thinning of corpus callosum in human patients.
Mislocalization of ATG9A (AP4 cargo) in AP4E1 KO mice is also seen in patient cells
|
Score
|
2 (2)
| null |
https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_be93d2e7-f302-41a7-9675-032510e46ad2-2020-12-16T170000.000Z
| 2,698 |
PubMed:29698489
|
Lentiviral Vector Rescue
|
Rescue Patient cells
|
Izawa K, et al., 2017, PMID: 28011863
|
The lentivirus induced surface expression of CD70 to levels comparable with those seen on LCLs from control donors
|
Score
|
1 (1)
| null |
https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_69aa819c-1f25-42fe-8469-4641fc088a57-2025-02-05T170000.000Z
| 2,989 |
PubMed:28011863
|
Zhang patient cells
|
Functional Alteration Patient cells
|
Zhang S, et al., 2023, PMID: 36579833
|
Quantitative analysis of the number, total area, average length and total signal intensity per visual field (0.143 mm2) of AChR clusters in C2C12 cells expressing WT-DOK7 or p.G64R-DOK7/p.G64R-DOK7 markedly reduced AChR clustering.
|
Score
|
1 (1)
| null |
https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_b40a6c0a-1152-4d29-8ba3-1136600085b9-2025-02-24T170000.000Z
| 3,017 |
PubMed:36579833
|
Wang_Functional Alteration
|
Functional Alteration Patient cells
|
Wang L, et al., 2020, PMID: 32788587
|
By day in vitro 52, affected organoids were noticeably smaller than unaffected organoids. By day in vitro 90, the majority of unaffected COs were >5 mm, while none of the affected COs were >5 mm, and most were <1 mm diameter.
|
Score
|
1 (1)
| null |
https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_c46ba676-3297-4e2c-a88f-bc479c32de60-2024-03-06T170000.000Z
| 1,459 |
PubMed:32788587
|
Serpas_2019_Plasma DNA Fragmentation by DNASE1 +DNASE1L3
|
Biochemical Function A
|
, , PMID: 30593563
|
DNASE1L3 is also an endonuclease capable of cleaving both single- and double-stranded DNA that has been strongly associated with SLE in a loss-of-function autosomal recessive pattern. This experiment shows the effect of deletions in DNASE1L3 only, DNASE1 only, DNASE1 + DNASE1L3, and WT mice on the degree of plasma DNA fragmentation, by showing the frequency of short plasma DNA fragments in each group of mice. The method used was paired-end sequencing followed by genome sequence alignment of both end sequences of each DNA molecule for fragment size determination. Mice with double deletions of DNASE1 + DNASE1L3 show the highest frequency of short plasma DNA fragments, suggesting a synergistic function of the two gene products.
|
Score
|
0.5 (0.5)
| null |
https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_b71d9246-5a7e-4e81-8fc6-925181d124cd-2024-06-14T190000.000Z
| 635 |
PubMed:30593563
|
ER localization
|
Biochemical Function B
|
Gerondopoulos A, et al., 2014, PMID: 24891604
|
Control and patient fibroblasts were fixed and stained with antibodies to CLIMP-63 and reticulon 4 (Rtn4). In comparison to control fibroblasts, CLIMP-63 spread away from the perinuclear region into the cell periphery and clearly defined Rtn4-positive tubules were lost in both the Rab18 L24Q and Rab3GAP1 (c.649-2A>G) patient cell lines (Fig. 7 a). Measurements of the area occupied by CLIMP- 63 indicated that ER sheet volumes increased from 20% of the cell area to 60–70% in cells with mutant Rab18 or Rab3GAP1 (Fig. 7 b). Spread of ER sheets and a loss of fragmentation of ER
tubules were therefore observed in patient fibroblasts.
|
Score
|
0.5 (0.5)
| null |
https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_a322fa3e-2985-4f60-9b4b-87f333cf9431-2023-11-28T200000.000Z
| 1,804 |
PubMed:24891604
|
Subcellular localization and pH homeostasis
|
Functional Alteration Non-patient cells
|
Prasad H, et al., 2017, PMID: 28815171
|
No subcellular localization or expression change was observed. No loss-of-function was observed with respect to endosomal pH homeostasis and transferrin endocytosis.
|
Score
|
0 (0.5)
|
No functional alteration observed for these variants.
|
https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_463ee005-1264-45da-bd85-3776a6637c68-2020-10-08T160000.000Z
| 2,030 |
PubMed:28815171
|
Mouse single cell transcriptomics
|
Expression A
|
de Soysa TY, et al., 2019, PMID: 31341279
|
Detection via single cell RNA sequencing
|
Score
|
0.5 (0.5)
| null |
https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_7a70bdb1-a3fc-45c5-aabb-4d2829fa6f29-2023-04-04T160000.000Z
| 961 |
PubMed:31341279
|
Electron cryomicroscopy structure of complex I
|
Biochemical Function A
|
Zhu J, et al., 2016, PMID: 27509854
|
Mammalian complex I contains 45 subunits, comprising 14 core subunits that house the catalytic machinery and are conserved from bacteria to humans, and a mammalian-specific cohort of 31 supernumerary subunits. Zhu et al. present a structural model of complex I.
|
Score
|
2 (0.5)
|
Scored 2 pts per scoring rubric (> 10 proteins associated with PMD)
|
https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_fbdf3ba5-37d8-447d-888b-2762701bab49-2022-03-07T050000.000Z
| 1,483 |
PubMed:27509854
|
Naturally occurring Nme5-related canine PCD model
|
Model Systems Non-human model organism
|
Anderegg L, et al., 2019, PMID: 31479451
|
Alaskan Malamutes harboring the homozygous variant in NME5 exhibit lack of situs inversus, severe bronchial lung pattern with bronchiectasis (Figure 1), hyperemia of the tracheal mucosa with high mucopurulent secretion along the upper and lower airways and nasal cavitiy (Figure 1). Bronchoalveolar bacterial cultures were consistent with chronic infections. Reduced ciliary number and rhinitis were observed in nasal mucosa. Affected animals also showed recurrent bacterial infections, abnormal axonemal organization including extra microtubules, and absent/shortened dynein arms.
|
Score
|
2 (2)
|
The degree of phenotypic match between the affected animals and the NME5-deficient human patients have led to a recommendation of default scoring. The variant was naturally occurring in Alaskan Malamutes rather than a targeted mutation, and has not been observed in an affected human patient.
|
https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_00efe110-5916-4da0-92ac-cee8c8b18140-2024-02-08T170000.000Z
| 1,542 |
PubMed:31479451
|
Expression of CCDC65 during ciliogenesis
|
Expression A
|
Horani A, et al., 2013, PMID: 23991085
| null |
Score
|
1 (0.5)
|
Two separate experiments validated the expression of CCDC65 in PCD relevant tissues and during ciliogenesis
|
https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_662ab516-ba5f-46aa-97b2-ef4c8f3201a5-2024-08-08T160000.000Z
| 327 |
PubMed:23991085
|
Yan_Mouse Model
|
Model Systems Non-human model organism
|
Yan L, et al., 2023, PMID: 37228654
|
The Wdr60 PB/PB embryos had much less cilia than WT embryos. The human phenotype is a skeletal ciliopathy, which is caused by defects in the function of cilia.
|
Score
|
2 (2)
| null |
https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_ad85ec94-69a9-4e67-a366-5ec2d574f1e4-2024-09-04T160000.000Z
| 669 |
PubMed:37228654
|
DICER KO MSC rescue
|
Rescue Cell culture model
|
JnBaptiste CK, et al., 2017, PMID: 28446596
|
miRNA expression was rescued and the endogenous targets of the miRNA, mRNA, expression pattern correlated with previous reported changes. doxorubicin-induced sensitivity (culminating in cell death) was also returned to wildtype levels. Some specific miRNA target mRNAs remained activated, authors explain as a 'stable state transformation' induced by DICER1 deletion.
|
Score
|
1 (1)
| null |
https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_aeabfc3b-63a9-40f2-9c71-41b079fee4e2-2023-07-05T170000.000Z
| 600 |
PubMed:28446596
|
Mitochondrial fusion assay
|
Functional Alteration Non-patient cells
|
Chen H, et al., 2003, PMID: 12527753
|
Two ovoid mitochondria contact each other but do not fuse until much later. Unfused mitochondria
|
Score
|
0.5 (0.5)
| null |
https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_a04350b3-5fe9-438a-9e90-db0055ed15e7-2022-10-10T160000.000Z
| 1,287 |
PubMed:12527753
|
DDOST variants affect LOX N-glycosylation
|
Functional Alteration Non-patient cells
|
Kas SM, et al., 2023, PMID: 37848450
|
LOX N-glycosylation was also restored by DDOST p.G200D, p.S206P and p.R379Q, but not by p.L364Ffs11 or p.I405Tfs7.
|
Score
|
0.5 (0.5)
| null |
https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_e0605b51-70c5-42ee-81b5-d45bb0b1fdab-2023-11-15T170000.000Z
| 2,987 |
PubMed:37848450
|
Depletion of p150 in mice neurons
|
Model Systems Non-human model organism
|
Yu J, et al., 2018, PMID: 29490687
|
The loss of SMN with a late onset, loss of motor control, muscle atrophy, and gliosis are all features commonly observed in patients with ALS.
|
Score
|
1 (2)
|
No differences of cerebral spinal motor neurons. Lack of clinical similarity to ALS (eg. lifespan)
|
https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_5cd19f2c-2499-417f-94c8-2bd4bedf34ef-2023-08-04T160000.000Z
| 583 |
PubMed:29490687
|
rhg mouse
|
Model Systems Non-human model organism
|
Bisaillon JJ, et al., 2014, PMID: 25264521
|
A missense variant in Oat, p.Gly353Ala, was found to be the cause of the “retarded hair growth” (rhg) phenotype in mice. Homozygous rhg mice appear normal at birth but they are smaller than their heterozygous littermates by 10 days of age, and have delayed development of a hairy coat that is most obvious at 7–10 days of age. This study found that adult rhg/rhg and rhg/Oat Δ mutants have profoundly elevated levels of plasma ornithine and decreased levels of plasma lysine similar to the levels previously reported for both mice and humans homozygous for recessive defects in Oat. Like human patients with OAT deficiency, who develop gyrate atrophy, histology of the retinas of rhg/rhg and rhg/OatΔ mice at 7 and 12 months of age showed evidence of retinal abnormalities including retinal pigment epithelium cells that were irregular in size and shape, and some appeared to have migrated into the outer segment layer, and photoreceptor outer segments that were shortened and disorganized.
|
Score
|
2 (2)
| null |
https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_edbab666-9ae6-46db-b818-809a4bf8333e-2019-07-10T160000.000Z
| 2,617 |
PubMed:25264521
|
Heterozygous conditonal deletion allele for Dynch1h1
|
Model Systems Non-human model organism
|
Di Pizio A, et al., 2023, PMID: 36218033
|
abnormal hind limb posture when suspended by the tail is indicative of motor phenotypes in mice
|
Score
|
1 (2)
|
Downgraded because the disease mechanism in patients is GoF probably and this is a LoF model (discussed at the CMT GCEP meeting)
|
https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_c1e12eb9-aea0-4597-8893-48df533f6ad9-2023-07-12T160000.000Z
| 668 |
PubMed:36218033
|
Global and tissue specific (multiciliated) CEP164 KO mouse
|
Model Systems Non-human model organism
|
Siller SS, et al., 2017, PMID: 29244804
|
At E9.5 and E10.5, CEP164-KO embryos exhibited holoprosencephaly, cardiac looping defects, an edematous pericardial sac, and a truncated posterior trunk. These phenotypes are similar to those reported for mouse mutants for KIF3A and KIF3B, which are major components of the kinesin-II ciliary anterograde motor, providing evidence for the essential role of CEP164 in primary ciliogenesis and for mammalian embryogenesis.
Specific ablation of CEP164 in multiciliated cells (CEP164fl/fl with Cre under FOXJ1 promoter) from the the airways, brain ventricles, oviducts and testis showed:
approx. 20% that succumbed to death due to severe hydrocephalus around weaning and another approx. 20% that exhibited mild hydrocephalus, which resolved itself later
substantial ventricular enlargement
A clear reduction in the number of ependymal multicilia
A marked decrease in the number of airway multicilia
Impaired mucociliary clearance
This is consistent with the primary ciliary dyskinesia/bronchiectasis phenotypes seen in patients
|
Score
|
2 (2)
| null |
https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_961b81f6-7ad1-49e2-b675-c035b4d8d35d-2021-10-27T160000.000Z
| 3,062 |
PubMed:29244804
|
Ektacytometry of patient RBCs
|
Functional Alteration Patient cells
|
Yamaguchi Y, et al., 2021, PMID: 34737711
|
Ektacytometry determined that patient red blood cells had increased H2O volume, reduced K+, increased Na+ consistent with increased channel activity.
|
Score
|
0.5 (1)
|
Reduced score as red blood cell phenotype consistent with DHS has also been described rarely for patients with homozygous loss of function PIEZO1 variants.
|
https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_6a86cb1d-4eed-4c10-971f-4a9578cb12b1-2023-07-02T040000.000Z
| 1,674 |
PubMed:34737711
|
Rnaseh2c-/- mice
|
Model Systems Non-human model organism
|
Hiller B, et al., 2012, PMID: 22802351
|
Although mouse phenotype was limited for knock-out model due to early embryonic lethality, cells obtained from knock-out mouse embryos demonstrated increased genomic ribonucleotide load consistent with underlying disease mechanism.
|
Score
|
2 (2)
| null |
https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_9f65b554-f11e-41ff-8a6f-dcb5d8484122-2024-08-26T160000.000Z
| 1,871 |
PubMed:22802351
|
BRWD1 mutated mice have hypogammaglobulinemia
|
Model Systems Non-human model organism
|
Mandal M, et al., 2015, PMID: 26301565
|
BRWD1 mutated mice show decreased levels of circulating antibodies like observed in human patients.
|
Score
|
2 (2)
| null |
https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_a44471f3-0951-4456-955d-916b691e59f5-2022-12-08T170000.000Z
| 255 |
PubMed:26301565
|
MTX2 and MTX1 deficiency hampers TNF-α-induced apoptosis
|
Functional Alteration Patient cells
|
Elouej S, et al., 2020, PMID: 32917887
|
The number of dead cells upon apoptosis was significantly reduced in patients compared to control fibroblasts, confirmed by the reduction of Caspase 3 cleavage in MTX2-mutant fibroblasts.
Observed Increased macro-autophagy in MTX2 deficient patient fibroblast cells.
The mitochondrial dysfunction and hampered apoptosis may account for the lipodystrophy and progeroid like features, hepatomegaly
|
Score
|
1 (1)
| null |
https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_95b2738d-c934-401b-8665-dd6a19ec6a05-2024-06-05T160000.000Z
| 1,410 |
PubMed:32917887
|
Gorelik_Lysosomal multienzyme complex
|
Biochemical Function A
|
Gorelik A, et al., 2021, PMID: 33980489
|
GLB1, CTSA and NEU1 form the lysosomal multienzyme complex together.
|
Score
|
0.5 (0.5)
|
GLB1 protein forms the lysosomal multienzyme complex with the products of two other genes, CTSA and NEU1. Increased points are awarded for the same function as two other genes causing lysosomal disorders.
|
https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_9e170fda-e08a-4fd3-a3e5-f08c5c0d55b8-2023-04-28T160000.000Z
| 901 |
PubMed:33980489
|
Zebrafish model
|
Model Systems Non-human model organism
|
Halbig KM, et al., 2012, PMID: 22268977
|
The Zebrafish demonstrates heart defects, ear abnormalities, and other bodily malformations that are also seen in humans.
|
Score
|
1.5 (2)
|
Downscored 0.5 points due to lack of laboratory phenotype reported within this model system.
|
https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_d2961595-2f51-45d6-af4d-988ec5a7628a-2024-03-05T170000.000Z
| 2,379 |
PubMed:22268977
|
Review: LeighMap
|
Biochemical Function A
|
Rahman J, et al., 2017, PMID: 27977873
|
Rahman et al. reviews all genes associated with Leigh syndrome in Leigh Map 2017 (PMID: 27977873). These genes included at least thirteen nuclear genes directly involved in mitochondrial translation as well as five additional mt-tRNA genes.
|
Score
|
2 (0.5)
|
per rubric: More than 10 gene with a related function
|
https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_42f2fc91-c26d-416c-8d93-448e4a52983b-2021-04-14T040000.000Z
| 1,394 |
PubMed:27977873
|
Impaired generation of memory B cells
|
Functional Alteration Patient cells
|
Cagdas D, et al., 2021, PMID: 33929673
|
Within the contracted memory B cell population in IL-21R-deficient patients, proportions of IgG+ or IgA+ switched cells were significantly decreased
|
Score
|
1 (1)
| null |
https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_4dbeac16-997c-43c0-9fb6-eaa98d0816f9-2022-12-31T120000.000Z
| 1,062 |
PubMed:33929673
|
Bach2 is required for efficient formation of Treg cells
|
Biochemical Function B
|
Roychoudhuri R, et al., 2013, PMID: 23728300
|
Impaired regulatory T cell function are evident in BACH2 mutant patients compared with healthy controls and also with patients with classical IBD
|
Score
|
0.5 (0.5)
| null |
https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_2473560a-6e5c-4342-a6e2-c89e37f4cc71-2023-02-21T180000.000Z
| 206 |
PubMed:23728300
|
Abkevich Expression
|
Expression B
|
Abkevich V, et al., 2012, PMID: 23047548
|
RAD51C promoter methylation was observed consistently in cohorts and the high homologous recombination deficiency (HRD) score showed a significant association with RAD51C deficiency in two data sets and was consistent with scores for BRCA1/2 defects also found in the data sets.
Ovarian tumors with LOH show increased homologous recombination rates.
Supplementary Table S4, Supplementary Figure S6,
|
Score
|
0.5 (0.5)
| null |
https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_31cb27be-dd32-4bb7-86bd-43c4b1eabaf5-2024-08-29T170000.000Z
| 1,814 |
PubMed:23047548
|
Wang 2016 knock-in mouse model
|
Model Systems Non-human model organism
|
Wang F, et al., 2016, PMID: 27469509
|
Developed a heterozygous knock-in transgenic mouse strain in which the R140Q (patient variant) was introduced into the native Idh2 locus.
Knock-in mice showed higher pre- and peri-natal mortality, runting, facial dysmorphism and abnormal head shape, cardiomyopathy, cardiomyocyte hypertrophy, vacuoles in brain tissue, hydronephrosis, and functional renal obstruction.
Plasma, bone marrow, brain, spleen, and heart from knock-in animals showed elevated 2-HG.
Administration of the selective and potent small molecule inhibitor of IDH2 R140Q mutant enzyme, AGI-026, which crosses the blood-brain barrier inhibited 2-HG production, improved survival, reduced incidence of cardiac abnormalities, and reduced numbers of brain sites affected by vacuolation.
|
Score
|
2 (2)
| null |
https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_91787b5b-8185-48e6-a437-9162c039b454-2023-01-30T170000.000Z
| 1,038 |
PubMed:27469509
|
Neurotransmitter alterations in Aldh5a1-/- mouse embryos
|
Model Systems Non-human model organism
|
Jansen EE, et al., 2008, PMID: 19040727
|
Succinic semialdehyde dehydrogenase deficiency is a disorder of the GABA degradation pathway where consecutive elevation of gamma-hydroxybutyric acid (GHB) and GABA occur. GABA and DHHA (4,5-dihydroxyhexanoic acid) were found to be significantly elevated at all gestational ages in Aldh5a1-/- mice,
|
Score
|
2 (2)
| null |
https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_c3e57466-df2f-4045-b374-010dbd334bfc-2021-04-27T160000.000Z
| 90 |
PubMed:19040727
|
BLOC-2 complex cargo delivery
|
Biochemical Function B
|
Dennis MK, et al., 2015, PMID: 26008744
|
Albinism in HPS patients reflects defects in the biogenesis of melanosomes in melanocytes of the skin, hair, and choroid of the eye and in pigment epithelial cells of the retina, iris, and ciliary body of the eye. While not addressed here, a similar cargo delivery mechanism may be involved in the bleeding and bruising which reflects the absence of detectable dense granules in platelets.
|
Score
|
0.5 (0.5)
|
Live-cell imaging analyses show that BLOC-2 is required for melanosome-destined tubular carriers to make stable contacts with maturing melanosomes. Consistently, BLOC-2 influences the melanosomal delivery of BLOC-1-dependent cargoes, including TYRP1, OCA2, ATP7A, and a cohort of TYR, from early endosomes in mouse melanocytes as observed in altered melanocytes from patients with HPS6. These results support a model in which BLOC-2 functions to direct recycling endosomal tubular transport intermediates to mature melanosomes and thereby promote cargo delivery and optimal pigmentation.
|
https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_a761e746-824f-496c-8d9f-4f8cd50423c3-2020-10-28T160000.000Z
| 1,016 |
PubMed:26008744
|
Ye knockout mouse
|
Model Systems Non-human model organism
|
Ye L, et al., 2015, PMID: 25811986
|
Global Snx10-deficiency in mice results in a combined phenotype of osteopetrosis (due to osteoclast defect) and rickets (due to high stomach pH and low calcium availability, resulting in impaired bone mineralization). Snx10 knockdown (KD) mice exhibited severe growth retardation with failed tooth eruption compared to WT or heterozygous controls. Snx10 KD mice die between 3 and 4 weeks post-partum with impaired gastric acidification and are severely hypocalcemic compared to wild type littermates. The overall skeletal development was impaired, with higher radio-density in the 3-week-old Snx10 KD mice (unresorbed trabecular bone, lacked marrow spaces, radiograph and by micro-CT of transverse sections of long bones (femur, tibia, humerus) revealed an inner ring of cortex-like (denser) bone within the trabecular consistent with a severely osteopetrotic human phenotype). Osteoclast-specific Snx10 knockout had no effect on calcium balance, and therefore led to severe osteopetrosis without rickets. Supplementation with calcium gluconate rescued mice from the rachitic phenotype and dramatically extended life span in global Snx10-deficient mice, suggesting that this may be a life-saving component of the clinical approach to Snx10-dependent human osteopetrosis that has previously gone unrecognized.
|
Score
|
2 (2)
| null |
https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_4c6f3ffa-405b-4b64-b29d-b4dc157ef586-2024-06-24T160000.000Z
| 2,063 |
PubMed:25811986
|
LRRC56 is part of mouse LRO transcriptome
|
Expression A
|
Bellchambers HM, et al., 2023, PMID: 37393374
|
Single cell RNA sequencing (scRNA-seq) was done to generate a transcriptomic profile list of LRO genes from precisely staged 0–1 somite mouse embryos, when the LRO fluid flow is first detected. LRRC56 was one of 196 transcripts described as the LRO transcriptome. LRO cells have motile cilia and are involved in determining embryo laterality. The expression of LRRC56 in the LRO is consistent with LRRC56 playing a role in determining human left right patterning.
|
Score
|
0.5 (0.5)
| null |
https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_ceef14a8-34d2-41ac-8c03-47c5eaff8986-2024-11-19T200000.000Z
| 1,227 |
PubMed:37393374
|
MMADHC crystal structure
|
Protein Interaction
|
Froese DS, et al., 2015, PMID: 26483544
|
A series of human MMADHC and MMACHC truncation proteins was expressed and interactions between them was assessed using blue native-PAGE and size-exclusion chromatography. The MMADHC region C-terminal to amino acid 154 and the MMACHC region without the C terminus was found to be sufficient for direct protein-protein interaction. Next, mouse MMADHC was analyzed by X-ray crystallography to further elucidate the MMACHC interaction. Key findings included that MMADHC binds Cbl-bound MMACHC after Cbl has been processed by MMACHC; and the MMACHC interaction region of MMADHC contains a modified nitrogen reductase (NTR) fold that abolishes homodimerization, and favors heterodimerization with another modified NTR fold from MMACHC. Of note, variants in MMACHC result in "methylmalonic aciduria and homocystinuria type cblC" (definitive gene-disease relationship based on assessment by the ClinGen Aminoacidopathy gene Curation Expert Panel.
|
Score
|
1 (0.5)
|
The score is increased due to the level of evidence available including multiple experimental approaches taken to analyze the interaction between MMADHC and MMACHC.
|
https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_40ec59af-a143-4424-9218-7fd75deb6a61-2021-05-12T182739.747Z
| 1,307 |
PubMed:26483544
|
Dnah5 siRNA knockout in mouse tracheal epithelial cells
|
Model Systems Cell culture model
|
Zahid M, et al., 2020, PMID: 32823934
|
High-speed video microscopy of cilia beating in human DNAH5 mutants shows a range of effects on cilia motility depending on the particular variants. Phenotypes can range from completely immotile respiratory cilia to altered motility with stiff movements and low amplitudes (Raidt et al PMID:25186273).
There was no significant change in ciliogenesis or cilia length with Dnah5 knockdown. However, approximately half of the ciliated cells were immotile. Where motile cilia were present, the ciliary beat frequency was normal, though some motile cilia exhibited dyskinetic ciliary motion (Supplementary Video S6 and S7).
|
Score
|
1 (1)
| null |
https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_4390dba1-012d-4e08-a841-ffc08ebdc737-2022-01-07T190607.723Z
| 624 |
PubMed:32823934
|
Mutant expression in endocrinepancreatic tumor of patient
|
Expression B
|
Occhi G, et al., 2013, PMID: 23555276
|
Endocrine pancreatic tumor of the patient having the c.-456_-453delCCTT mutation. Tumor cells show low expression of p27KIP1 in the nucleus but also expression in the cytoplasm. (Fig. 4).
|
Score
|
0.5 (0.5)
| null |
https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_b07f8882-dd5e-4831-9926-f8b4c2a8c265-2018-12-21T154854.477Z
| 364 |
PubMed:23555276
|
Immunostaining analysis
|
Expression A
|
Porpora M, et al., 2018, PMID: 29581457
|
Immunostaining analysis confirmed significant fraction of NEK10 is localized at cilia. Serum deprived HEK293 cells were immunostained and acetylated tubulin and analyzed by confocal microscope.
|
Score
|
0.1 (0.5)
|
Recognize as independent assay but showing same datapoint as Chivukula 2020 paper.
|
https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_72a2f8fa-ee83-48cc-93fa-22a8990c8d13-2023-07-13T160000.000Z
| 2,827 |
PubMed:29581457
|
Neuron KO of MICU1 in Mice
|
Model Systems Non-human model organism
|
Singh R, et al., 2022, PMID: 35302860
|
Mice should abnormal calcium flux and diminished function on rotarod test and grip test
|
Score
|
1 (2)
|
Score 0.5 for calcium flux abnormalities, Score 0.5 for phenotype
|
https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_4c9276ee-39e6-408f-9ae0-a4c3000f3089-2023-11-20T050000.000Z
| 1,293 |
PubMed:35302860
|
Wnt5a in canonical and non-canonical signaling
|
Biochemical Function A
|
Mikels AJ, et al., 2006, PMID: 16602827
|
The impact of Wnt5a ligand on Wnt signaling was studied in mouse cells and HEK293 cells. STF-luciferase assay was used as a readout of beta-catenin activity. Wnt3a expression activaed the canonical pathway. However, over-expression of Wnt5a inhibited canonical Wnt signaling by Wnt3a in mouse cells (Fig 1). Frizzled 4 receptor was exogenously expressed in 293 cells (293Fz4), and were treated with Wnt proteins, followed by assay for cytosolic beta-catenin protein accumulation via Western blot analysis. Wnt5a treatment led to beta-catenin stabilization specifically in cells expressing mFz4 (Fig 4a). Wnt5a at different dosage concentrations did not inhibit Wnt3a-mediated reporter activation in 293Fz4 cells (Fig 4c). TheWnt5a treatment also activated the STF reporter when LRP5 was coexpressed, but not when LRP6 was co-expressed (Fig 4b). Exogenous expression of mRor2 in HEK293 cells, followed by immunoprecipitation and STF-luciferase assay demonstrated that signaling through the Wnt5a-Ror2 interaction is required for inhibition of canonical Wnt signaling (Fig 5 and 6).ROR2 is the receptor for WNT5A (PMID 12839624).
|
Score
|
0.5 (0.5)
| null |
https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_0fb2940f-f0e0-442c-beb8-72fc959d5a43-2024-04-25T160000.000Z
| 2,932 |
PubMed:16602827
|
Mutant CHCHD10 on TDP43 apoptosis and synaptic damange
|
Protein Interaction
|
Woo JA, et al., 2017, PMID: 28585542
|
Wild-type CHCHD10 ameliorates and FTD/ALS CHCHD10 mutations potentiate TDP-43-induced apoptosis and synaptic impairment
|
Score
|
0.5 (0.5)
| null |
https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_d154f67a-25ce-40d3-9de3-1f001753843a-2022-09-13T160000.000Z
| 398 |
PubMed:28585542
|
Mitochondrial translation defects
|
Biochemical Function A
|
D'Souza AR, et al., 2018, PMID: 30030363
|
Mitochondrial tRNA
|
Score
|
2 (0.5)
|
Mitochondrial translation defects are a known cause of primary mitochondrial disease.
|
https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_99e85f3e-3c1f-4265-8b70-0870e95d4c30-2023-04-17T160000.000Z
| 1,393 |
PubMed:30030363
|
DSB repair measurements
|
Functional Alteration Patient cells
|
Keupp K, et al., 2019, PMID: 31347298
|
two fold decrease in HR was scored for the LCLs from the mother carrying the BRCA1 p.Arg1699Gln mutation and sixfold for the LCLs from the index patient carrying both mutations; in addition, both LCLs showed four‐ to fivefold elevated microhomology‐mediated end joining compared with three wild‐type LCLs
|
Score
|
1 (1)
| null |
https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_aa39798d-9b6e-430d-8bc1-2a01f81f1f72-2020-05-14T003137.538Z
| 2,525 |
PubMed:31347298
|
Alx expression in the developing head of mouse, chick, and f
|
Expression A
|
McGonnell IM, et al., 2011, PMID: 21740507
|
Probands with mutant ALX3 alleles showcase defects in the are expressed in the mesenchyme of the facial prominences, particularly around the nasal region and at the distal tip of the mandible. Regular expression of ALX3 has been confirmed by multiple mouse models: Ten Berge et al. (1998) PMID:PMID: 9676189 and Beverdam et al. (2001) (PMID:11641221)
|
Score
|
0.5 (0.5)
| null |
https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_1b460912-d5fd-4b7b-99da-ccd477fd8139-2022-10-13T160000.000Z
| 108 |
PubMed:21740507
|
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