Submissions for variant NM_004004.6(GJB2):c.283G>A (p.Val95Met)

gnomAD frequency: 0.00008  dbSNP: rs111033299

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000211719	SCV000061496	pathogenic	Rare genetic deafness	2017-05-02	criteria provided, single submitter	clinical testing	The p.Val95Met variant in GJB2 has been reported in the compound heterozygous st ate in at least 19 individuals with hearing loss and segregated in at least thre e affected relatives (Cheng 2005, Cryns 2004, Kelley 1998, Lemonnier 1990, Marli n 2005, Oliveira 2002, Pandya 2003, Wang 2003, LMM data). This variant has been identified in multiple ethnic groups with a highest frequency of 5/33580 of Lati no chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadin stitute.org; dbSNP rs111033299). Although this variant has been seen in the gene ral population, its frequency is low enough to be consistent with a carrier freq uency for autosomal recessive nonsyndromic hearing loss. In summary, this varian t meets criteria to be classified as pathogenic for nonsyndromic hearing loss in an autosomal recessive manner based upon biallelic observations in affected ind ividuals, segregation evidence, and low frequency in the general population. ACM G/AMP Criteria applied: PP1, PP3, PM2, PM3_VS.
Genetic Services Laboratory, University of Chicago	RCV000146014	SCV000193165	pathogenic	Hearing impairment	2013-02-08	criteria provided, single submitter	clinical testing
Counsyl	RCV000037834	SCV000220868	likely pathogenic	Autosomal recessive nonsyndromic hearing loss 1A	2014-11-07	criteria provided, single submitter	literature only
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000516830	SCV000603835	pathogenic	not provided	2018-02-09	criteria provided, single submitter	clinical testing	The GJB2 c.283G>A; p.Val95Met variant has been reported multiple times in the literature in individuals and families with hearing loss who were compound heterozygous with another pathogenic variant (Cheng 2005, Kelley 1998, Oliveira 2002, Putcha 2007, Snoeckx 2005). Additionally, functional studies suggest the variant protein affects biochemical coupling, but has little or no effect on intercellular conductance of gap junctions (Zhang 2005, Wang 2003). This variant has been reported to the ClinVar database (Variation ID: 44735), and is observed in the general population databases at a frequency of 0.005% (rs111033299, Genome Aggregation Database). The valine at codon 95 is well conserved across species, and computational algorithms predict this variant to be damaging to the protein (SIFT, PolyPhen2, MutationTaster). Taken together, this variant is considered pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV000515247	SCV000611270	pathogenic	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	2017-05-18	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000516830	SCV000613510	pathogenic	not provided	2016-08-26	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000516830	SCV000936055	pathogenic	not provided	2025-01-12	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 95 of the GJB2 protein (p.Val95Met). This variant is present in population databases (rs111033299, gnomAD 0.01%). This missense change has been observed in individuals with autosomal recessive nonsyndromic deafness (PMID: 11216656, 14985372, 23668481, 27398341). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 44735). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt GJB2 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects GJB2 function (PMID: 16217030). For these reasons, this variant has been classified as Pathogenic.
INGEBI, INGEBI / CONICET	RCV001257560	SCV001434014	pathogenic	Nonsyndromic genetic hearing loss	2020-08-21	criteria provided, single submitter	clinical testing	Based on ACMG/AMP guidelines and Hearing Loss Expert Panel specific criteria: the filter allele sequence of the c.283G>A p.(Val95Met) in GJB2 gene is 0,0056% (5/34590 alleles in Latino population with 95% CI) in Genome Aggregation Database (http://gnomad.broadinstitute.org; calculated by using inverse allele frequency at https://www.cardiodb.org/allelefrequencyapp/), meeting PM2 criteria. This variant was identified in trans with several pathogenic variants in at least 10 patients with non-syndromic hearing loss (PM3_VeryStrong; PMID: 9529365, 11216656, 12081719, 12239718, 14985372, 15967879, 16380907, 20234132, 26043044, 24158611). This change in trans with pathogenic variants segregated in two siblings in two different families applying to PP1_Supporting (PMID:9529365, 11216656). Computational evidence predicted a pathogenic effect of the variant to the protein (REVELscore: 0.894; PP3). Functional studies showed that V95M mutant formed functional channels that were permeable to fluorescent tracers in transfected N2A cells and conductance measure similar to WT-Cx26. However, reduce permeability to larger molecules was demonstrated (PMID: 12562518, 16217030). Therefore, functional data was not counted. Therefore, this variant meets criteria to be classified as pathogenic for autosomal recessive non-syndromic hearing loss (PM2, PM3_VeryStrong, PP1_Supporting and PP3)
New York Genome Center	RCV000037834	SCV001761051	pathogenic	Autosomal recessive nonsyndromic hearing loss 1A	2020-07-10	criteria provided, single submitter	clinical testing
GeneDx	RCV000516830	SCV001871336	pathogenic	not provided	2024-11-07	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect on the ion permeability of gap junction channels formed by the mutant GJB2 protein (PMID: 16217030); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 16217030, 12562518, 9529365, 31589614, 29871260, 25388846, 27792752, 12081719, 14985372, 16380907, 15967879, 11439000, 16125251, 11102979, 12239718, 20234132, 19887791, 25401782, 15150777, 19235794, 16222667, 15365987, 17041943, 11216656, 22695344, 16931589, 26043044, 12325027, 18983339, 19371219, 23668481, 22613756, 27843504, 30609409, 30168495, 24256046, 26117665, 11134236, 24156272, 21465647, 17567887, 31370293, 27398341, Ullah2015[Review], 26399936, 31160754, 33096615, 37892203, 34308104, 37106706, Perea2007[Case_report], 23503914, 24158611, 21481246, 34599368, 34515852, 36048236)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000037834	SCV002511670	pathogenic	Autosomal recessive nonsyndromic hearing loss 1A	2022-04-27	criteria provided, single submitter	clinical testing	Variant summary: GJB2 c.283G>A (p.Val95Met) results in a conservative amino acid change located in the Connexin, N-terminal domain (IPR013092) 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 4.8e-05 in 251540 control chromosomes (gnomAD, Cheng_2005, Kelley_1998). This frequency is not significantly higher than expected for a pathogenic variant in GJB2 causing Autosomal Recessive Non-Syndromic Hearing Loss (4.8e-05 vs 0.025), allowing no conclusion about variant significance. c.283G>A has been reported in the literature in multiple individuals affected with Autosomal Recessive Non-Syndromic Hearing Loss (e.g. Castro_2013, Cheng_2005, Cryns_2004, Kelley_1998, Dalamon_2013). These data indicate that the variant is very likely to be associated with disease. One publication reports that the variant negatively impacted large molecule trafficking across gap junctions, thereby disrupting gap junction mediated intracellular signaling (Zhang_2005). Nine ClinVar submitters have assessed the variant since 2014: all have classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Revvity Omics, Revvity	RCV000516830	SCV003834607	likely pathogenic	not provided	2021-11-30	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000516830	SCV004033237	pathogenic	not provided	2023-08-01	criteria provided, single submitter	clinical testing	GJB2: PM3:Very Strong, PM2, PP1
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000037834	SCV005399027	pathogenic	Autosomal recessive nonsyndromic hearing loss 1A	2024-10-10	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.5, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with both deafness and skin conditions (OMIM). Dominant negative is also a suggested mechanism (PMID: 28428247). (I) 0108 - This gene is associated with both recessive and dominant disease. The autosomal dominant diseases are commonly associated with pathogenic missense variants. The autosomal recessive disease is associated with bi-allelic loss-of-function variants and includes missense and protein truncating variants (NIH Genetics Home Reference, PMID: 12792423). (I) 0112 - The condition associated with this gene has incomplete penetrance (PMID:31160754). (I) 0115 - Variants in this gene are known to have variable expressivity. Severity can range from mild to profound with intrafamilial variability also commonly seen. Commonly, truncating variants are associated to a more severe hearing loss (PMID: 20301449). (I) 0200 - Variant is predicted to result in a missense amino acid change from valine to methionine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v4) <0.01 (78 heterozygotes, 0 homozygotes). (SP) 0309 - Multiple alternative amino acid changes at the same position has been observed in gnomAD (v4) (highest allele count: 2 heterozygotes, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated connexin domain (DECIPHER). (I) 0801 - This variant has very strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported pathogenic in >10 unrelated individuals with hearing loss (ClinVar, Deafness Variation database), and has been reported compound heterozygous with other well-known pathogenic variants in individuals with hearing loss (PMID: 24156272). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Fulgent Genetics, Fulgent Genetics	RCV005007955	SCV005634668	pathogenic	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	2024-04-29	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000037834	SCV002086055	pathogenic	Autosomal recessive nonsyndromic hearing loss 1A	2020-04-29	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004734552	SCV005366389	pathogenic	GJB2-related disorder	2024-08-02	no assertion criteria provided	clinical testing	The GJB2 c.283G>A variant is predicted to result in the amino acid substitution p.Val95Met. This variant has been reported as causative for autosomal recessive hearing loss (Kelley et al. 1998. PubMed ID: 9529365; Oliveira et al. 2002. PubMed ID: 12081719; Pandya et al. 2003. PubMed ID: 12865758; Cryns et al. 2004. PubMed ID: 14985372; Marlin et al. 2005. PubMed ID: 15967879; Figueroa-Ildefonso et al. 2019. PubMed ID: 31370293). Functional studies found this variant does not affect gap junction formation or ionic permeability, but does reduce the intercellular exchange of larger molecules (Wang et al. 2003. PubMed ID: 12562518; Zhang et al. 2005. PubMed ID: 16217030). This variant is reported in 0.014% of alleles in individuals of Latino descent in gnomAD. This variant is interpreted as pathogenic.