ClinVar Miner

Submissions for variant NM_001846.4(COL4A2):c.4987G>A (p.Gly1663Ser)

gnomAD frequency: 0.00043  dbSNP: rs12877501
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Laboratory Services, Illumina RCV000274759 SCV000382707 benign Porencephaly 2 2018-01-13 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Invitae RCV000892490 SCV001036362 likely benign not provided 2024-01-16 criteria provided, single submitter clinical testing
Institute of Human Genetics, University of Leipzig Medical Center RCV000274759 SCV001440229 likely benign Porencephaly 2 2019-01-01 criteria provided, single submitter clinical testing
CeGaT Center for Human Genetics Tuebingen RCV000892490 SCV002497691 uncertain significance not provided 2022-10-01 criteria provided, single submitter clinical testing
Mendelics RCV002248612 SCV002518132 uncertain significance not specified 2022-05-04 criteria provided, single submitter clinical testing
Ambry Genetics RCV002520862 SCV003643749 likely benign Inborn genetic diseases 2022-01-19 criteria provided, single submitter clinical testing This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV002248612 SCV004222823 benign not specified 2023-11-17 criteria provided, single submitter clinical testing Variant summary: COL4A2 c.4987G>A (p.Gly1663Ser) results in a non-conservative amino acid change located in the collagen IV, non-collagenous domain (IPR001442) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00072 in 1613506 control chromosomes (i.e. over 1100 individuals), including 3 homozygotes, and found predominantly at a frequency of 0.00093 within the Non-Finnish European subpopulation in the gnomAD database (v4.0). This data strongly suggests the variant is unlikely to be associated with a penetrant autosomal dominant condition and is instead a benign polymorphism found primarily in individuals of Non-Finish European ancestry. To our knowledge, no occurrence of c.4987G>A in individuals affected with Porencephaly 2 and no experimental evidence demonstrating its impact on protein function have been reported. Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Four submitters classified the variant as benign/likely benign and two classified it as uncertain significance. Based on the evidence outlined above, the variant was classified as benign.
Rare Disease Group, Clinical Genetics, Karolinska Institutet RCV000677259 SCV000681428 likely pathogenic Optic nerve hypoplasia flagged submission research

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