Submissions for variant NM_000091.5(COL4A3):c.4295G>A (p.Arg1432His)

gnomAD frequency: 0.00080  dbSNP: rs200509072

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000597767	SCV000707547	uncertain significance	not provided	2017-04-03	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000764365	SCV000895399	uncertain significance	Autosomal dominant Alport syndrome; Autosomal recessive Alport syndrome; Benign familial hematuria	2018-10-31	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000597767	SCV001067203	likely benign	not provided	2024-01-21	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001174854	SCV001338244	likely benign	not specified	2020-02-03	criteria provided, single submitter	clinical testing	Variant summary: COL4A3 c.4295G>A (p.Arg1432His) results in a non-conservative amino acid change located in the last collagen triple helix repeat (IPR008160) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00038 in 280924 control chromosomes, predominantly at a frequency of 0.003 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 1.4 fold of the estimated maximal expected allele frequency for a pathogenic variant in COL4A3 causing Alport Syndrome (autosomal recessive) phenotype (0.002), strongly suggesting that the variant is a benign polymorphism. To our knowledge, no occurrence of c.4295G>A in individuals affected with Alport Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Based on the evidence outlined above, the variant was classified as likely benign.
GeneDx	RCV000597767	SCV001778576	likely benign	not provided	2021-06-17	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV001276574	SCV001462973	likely benign	Autosomal dominant Alport syndrome	2020-04-24	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003952993	SCV004772165	likely benign	COL4A3-related disorder	2021-05-05	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).