Submissions for variant NM_004004.6(GJB2):c.457G>A (p.Val153Ile)

gnomAD frequency: 0.00414  dbSNP: rs111033186

Total submissions: 22

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000037857	SCV000061519	benign	not specified	2015-05-28	criteria provided, single submitter	clinical testing	p.Val153Ile in exon 2 of GJB2: This variant has been reported in the literature as both a benign polymorphism (Connexins and Deafness Website and other reports) as well as a pathogenic variant (Snoeckx 2005 and other reports). Several repor ts show that this variant occurs at an equal frequency in both hearing loss prob ands and the general population (Guerci 2007, Abidi 2008, RamShankar 2003, Roux 2004, Rickard 2001). It was also identified in 5.6% (922/16488) of South Asian c hromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute .org; dbSNP rs111033186), including 31 homozygous individuals. Functional studie s have demonstrated no impact to synthesis and localization of the connexin 26 p rotein (Guerci 2007). It has also been reported in a homozygous state in 3 indiv iduals with normal hearing (Guerci 2007, RamShankar 2003) as well as identified as a compound heterozygote in a normal hearing individual with the p.Met34Thr mu tation (Malikova 2004). And finally, this variant did not segregate with hearing loss in two kindreds (Gasmelseed 2004, Malikova 2004). In summary, these data s uggest that the p.Val153Ile variant is benign.
Eurofins Ntd Llc (ga)	RCV000037857	SCV000112274	benign	not specified	2012-12-18	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000037857	SCV000193176	benign	not specified	2013-02-08	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000037857	SCV000309917	benign	not specified		criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000270707	SCV000383002	benign	Autosomal dominant nonsyndromic hearing loss 3A	2018-03-06	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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000505519	SCV000599753	benign	Autosomal recessive nonsyndromic hearing loss 1A	2017-05-09	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000755275	SCV000603811	benign	not provided	2023-11-27	criteria provided, single submitter	clinical testing
GeneDx	RCV000755275	SCV000977441	benign	not provided	2018-03-27	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.
Athena Diagnostics	RCV000037857	SCV001143670	benign	not specified	2024-11-07	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001109786	SCV001267155	benign	Ichthyosis, hystrix-like, with hearing loss	2018-03-06	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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Illumina Laboratory Services, Illumina	RCV000505519	SCV001267156	likely benign	Autosomal recessive nonsyndromic hearing loss 1A	2018-03-06	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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
INGEBI, INGEBI / CONICET	RCV001257148	SCV001433664	benign	Nonsyndromic genetic hearing loss	2020-08-31	criteria provided, single submitter	clinical testing	Based on ACMG/AMP guidelines and Hearing Loss Expert Panel specific criteria: the filtering allele frequency of c.457G>A p.Val153Ile in GJB2 gene is 5% (1642/30610 Southeast Asian chromosomes with 95% CI) from Genome Aggregation Database (http://gnomad.broadinstitute.org; calculated by using inverse allele frequency at https://www.cardiodb.org/allelefrequencyapp/)), which meets the allele frequency threshold defined by the ClinGen Hearing Loss Expert Panel for considering very strong evidence against pathogenicity for autosomal recessive hearing loss variants (BA1). Functional studies demonstrated that mutants lost their abilities to form functional gap junction channels (PMID: 15241677). However, it was shown that there were not differences between p.Val153Ile mutant and wild-type results in dye transfer assay (Guerci V.I, et al 2007). Therefore, functional data was not counted. Besides, the p.Val153Ile change was detected in trans with c.35delG and in homozygous state in normal-hearing individuals applying to BS2 rule (PMID:11493200, 12746422). In summary, this variant meets criteria to be classified as benign for autosomal recessive non-syndromic hearing loss (BA1 and BS2).
Labcorp Genetics (formerly Invitae), Labcorp	RCV000755275	SCV001718430	benign	not provided	2025-01-29	criteria provided, single submitter	clinical testing
Pars Genome Lab	RCV000505519	SCV001749996	likely benign	Autosomal recessive nonsyndromic hearing loss 1A	2021-07-01	criteria provided, single submitter	clinical testing
Pars Genome Lab	RCV000270707	SCV001749997	benign	Autosomal dominant nonsyndromic hearing loss 3A	2021-07-01	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002496603	SCV002805646	benign	Autosomal recessive nonsyndromic hearing loss 1A; Mutilating keratoderma; Ichthyosis, hystrix-like, with hearing loss; Autosomal dominant keratitis-ichthyosis-hearing loss syndrome; Palmoplantar keratoderma-deafness syndrome; Knuckle pads, deafness AND leukonychia syndrome; Autosomal dominant nonsyndromic hearing loss 3A; X-linked mixed hearing loss with perilymphatic gusher	2022-05-11	criteria provided, single submitter	clinical testing
Breakthrough Genomics, Breakthrough Genomics	RCV000755275	SCV005219302	likely benign	not provided		criteria provided, single submitter	not provided
University of Washington Center for Mendelian Genomics, University of Washington	RCV001291334	SCV001479808	likely pathogenic	Hearing loss, autosomal recessive		no assertion criteria provided	research
Clinical Genetics, Academic Medical Center	RCV000037857	SCV001924668	benign	not specified		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000037857	SCV001960037	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000037857	SCV001974298	benign	not specified		no assertion criteria provided	clinical testing
Natera, Inc.	RCV000505519	SCV002086044	benign	Autosomal recessive nonsyndromic hearing loss 1A	2019-11-14	no assertion criteria provided	clinical testing