ClinVar Miner

Submissions for variant NM_004004.6(GJB2):c.283G>A (p.Val95Met) (rs111033299)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare 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 Deafness, autosomal recessive 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 Deafness, autosomal recessive 1A; Mutilating keratoderma; Hystrix-like ichthyosis with deafness; Keratitis-ichthyosis-deafness syndrome, autosomal dominant; Palmoplantar keratoderma-deafness syndrome; Knuckle pads, deafness AND leukonychia syndrome; Deafness, autosomal dominant 3a; Deafness, X-linked 2 2017-05-18 criteria provided, single submitter clinical testing
Athena Diagnostics Inc RCV000516830 SCV000613510 pathogenic not provided 2016-08-26 criteria provided, single submitter clinical testing
Invitae RCV000516830 SCV000936055 pathogenic not provided 2020-10-01 criteria provided, single submitter clinical testing This sequence change replaces valine with methionine at codon 95 of the GJB2 protein (p.Val95Met). The valine residue is highly conserved and there is a small physicochemical difference between valine and methionine. This variant is present in population databases (rs111033299, ExAC 0.02%). This variant has been observed in individual(s) with autosomal recessive nonsyndromic deafness (PMID: 14985372,11216656, 23668481, 27398341). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 44735). Experimental studies have shown that this variant affects GJB2 protein function (PMID: 16217030). For these reasons, this variant has been classified as Pathogenic.
INGEBI, INGEBI / CONICET RCV001257560 SCV001434014 pathogenic Nonsyndromic hearing loss and deafness 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 Deafness, autosomal recessive 1A 2020-07-10 criteria provided, single submitter clinical testing
GeneDx RCV000516830 SCV001871336 pathogenic not provided 2021-06-08 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 (Zhang et al., 2005); 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, 27535533, 31160754, 31370293, 30168495, 30609409, 25401782, 23668481, 11102979, 16125251, 11439000, 18983339, 12239718, 15967879, 16380907, 14985372, 12081719, 25388846, 27792752, 16222667, 9529365, 12562518, 21465647, 17567887, 11134236, 24156272, 26117665, 27843504, 24256046, 12325027, 22613756, 16931589, 11216656, 26043044, 19235794, 15150777, 15365987, 22695344, 17041943, 19887791, 20234132, 19371219)

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