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

gnomAD frequency: 0.00573  dbSNP: rs77964815

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
PreventionGenetics, part of Exact Sciences	RCV000253369	SCV000302078	likely benign	not specified		criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham 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	RCV000960013	SCV000732312	benign	not provided	2019-01-30	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 17216251, 19525337, 14582039, 30661074, 12028435, 14871398, 30467950)
Invitae	RCV000960013	SCV001106958	benign	not provided	2024-01-31	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, 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.
CeGaT Center for Human Genetics Tuebingen	RCV000960013	SCV002585864	benign	not provided	2024-05-01	criteria provided, single submitter	clinical testing	COL4A3: BS1, BS2
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002294102	SCV002587147	likely benign	Kidney disorder	2020-04-01	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002494692	SCV002798636	likely benign	Autosomal dominant Alport syndrome; Autosomal recessive Alport syndrome; Benign familial hematuria	2022-04-06	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000960013	SCV001926900	likely benign	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000960013	SCV001955462	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000960013	SCV001970112	likely benign	not provided		no assertion criteria provided	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000253369	SCV003839365	likely benign	not specified	2022-05-27	no assertion criteria provided	clinical testing