Submissions for variant NM_004004.6(GJB2):c.37G>A (p.Val13Met)

gnomAD frequency: 0.00010  dbSNP: rs768130937

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000779131	SCV000915628	uncertain significance	Autosomal recessive nonsyndromic hearing loss 1A	2018-11-21	criteria provided, single submitter	clinical testing	The GJB2 c.37G>A (p.Val13Met) missense variant was reported in a single study in a cohort of 7,401 North American individuals with hearing loss where it was found in a compound heterozygous state with a second known pathogenic missense variant in one affected individual (Putcha et al. 2007). The p.Val13Met variant occurs in a highly conserved region and is predicted by multiple prediction algorithms to be deleterious (Yilmaz et al. 2015). Control data are unavailable for this variant which is reported at a frequency of 0.00121 in the Latino population of the Exome Aggregation Consortium. Based on the limited evidence, the p.Val13Met variant is classified as a variant of unknown significance but suspicious for pathogenicity for a recessive form of nonsyndromic hearing loss. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Illumina Laboratory Services, Illumina	RCV001112644	SCV001270328	likely benign	Ichthyosis, hystrix-like, with hearing loss	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). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Illumina Laboratory Services, Illumina	RCV001112645	SCV001270329	likely benign	Autosomal dominant nonsyndromic hearing loss 3A	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). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001193185	SCV001361877	uncertain significance	not specified	2019-07-26	criteria provided, single submitter	clinical testing	Variant summary: GJB2 c.37G>A (p.Val13Met) results in a conservative amino acid change located in the Connexin, N-terminal domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 9.6e-05 in 249454 control chromosomes, predominantly at a frequency of 0.00061 within the Latino subpopulation in the gnomAD database. This frequency is not significantly higher than expected for a pathogenic variant in GJB2 causing Non-Syndromic Hearing Loss (9.6e-05 vs 0.026), allowing no conclusion about variant significance. c.37G>A has been reported in the literature in one individual affected with Non-Syndromic Hearing Loss (Putcha_2007). This report does not provide unequivocal conclusions about association of the variant with Non-Syndromic Hearing Loss. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar (after 2014), classifying the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Baylor Genetics	RCV000779131	SCV001524670	uncertain significance	Autosomal recessive nonsyndromic hearing loss 1A	2019-05-10	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Natera, Inc.	RCV000779131	SCV002086071	uncertain significance	Autosomal recessive nonsyndromic hearing loss 1A	2020-11-03	no assertion criteria provided	clinical testing