ClinVar Miner

Submissions for variant NM_000091.5(COL4A3):c.4484A>G (p.Gln1495Arg) (rs77964815)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
PreventionGenetics,PreventionGenetics RCV000253369 SCV000302078 likely benign not specified criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000253369 SCV000711947 likely benign not specified 2016-03-21 criteria provided, single submitter clinical testing p.Gln1495Arg in exon 49 of COL4A3: This variant is not expected to have clinical significance because it has been identified in 1.01% (671/66718) of European ch romosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute. org; dbSNP rs77964815).
GeneDx RCV000253369 SCV000732312 likely benign not specified 2018-01-22 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Invitae RCV000960013 SCV001106958 benign not provided 2020-12-05 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV001136778 SCV001296648 benign Alport syndrome 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000253369 SCV001554542 likely benign not specified 2021-03-30 criteria provided, single submitter clinical testing Variant summary: COL4A3 c.4484A>G (p.Gln1495Arg) results in a conservative amino acid change located in the Collagen IV, non-collagenous domain (IPR001442) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0063 in 249324 control chromosomes in the gnomAD database, including 9 homozygotes. The observed variant frequency is approximately 3.2 fold of the estimated maximal expected allele frequency for a pathogenic variant in COL4A3 causing Alport Syndrome, Autosomal Recessive phenotype (0.0019), strongly suggesting that the variant is benign. At-least one publication reports c.4484A>G with incomplete segregation, variable penetrance and non-informative phenotypes ranging from type-I diabetes, focal segmental glomerulosclerosis, microscopic hematuria, with normal renal function, normal hearing and no ocular abnormalities among in individuals in a family reportedly diagnosed with Alport Syndrome (Choi_2019). Furthermore, the variant did not segregate in an autosomal recessive manner in this family and the authors suggest a possible digenic association of this variant with another variant in the COL4A5 gene. No conclusions can be drawn from these data and this report does not provide unequivocal evidence supporting an association of this variant with Alport syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign (n=2)/likely benign (n=2). None of the submitters has cited the report utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as likely benign.

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