Submissions for variant NM_000091.5(COL4A3):c.4825C>A (p.Arg1609=)

dbSNP: rs756231749

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000369300	SCV000428197	uncertain significance	Alport syndrome	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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
GeneDx	RCV000657998	SCV000779769	uncertain significance	not provided	2023-09-01	criteria provided, single submitter	clinical testing	In silico analysis supports that this variant does not alter splicing; Has not been previously published as pathogenic or benign to our knowledge
Labcorp Genetics (formerly Invitae), Labcorp	RCV000657998	SCV001126562	benign	not provided	2024-01-22	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002469133	SCV002766590	likely benign	not specified	2022-11-02	criteria provided, single submitter	clinical testing	Variant summary: COL4A3 c.4825C>A alters a conserved nucleotide resulting in a synonymous change. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00018 in 249414 control chromosomes, predominantly within the Ashkenazi Jewish subpopulation at a frequency of 0.0034, within the gnomAD database. This frequency is approximately 2 fold of the maximum expected allele frequency for a pathogenic variant in COL4A3 causing autosomal recessive Alport Syndrome (0.0034 vs 0.0019), suggesting this may be a benign variant found most commonly within individuals of Askenazki Jewish ancestry. To our knowledge, no occurrence of c.4825C>A in individuals affected with Alport Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Three laboratories classified the variant as VUS and one classified it as benign. Based on the evidence outlined above, the variant was classified as likely benign.
Natera, Inc.	RCV001276580	SCV001462979	uncertain significance	Autosomal dominant Alport syndrome	2020-04-24	no assertion criteria provided	clinical testing