ClinVar Miner

Submissions for variant NM_004004.6(GJB2):c.677T>G (p.Val226Gly)

gnomAD frequency: 0.00002  dbSNP: rs773846324
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Hearing Loss Variant Curation Expert Panel RCV000710340 SCV000840534 uncertain significance Nonsyndromic genetic hearing loss 2023-09-26 reviewed by expert panel curation The c.677T>G variant in GJB2 is a missense variant predicted to cause substitution of valine to glycine at amino acid 226. The highest population minor allele frequency in gnomAD v2.1.1 is 0.003% (1/35370) in Latino/Admixed American chromosomes, which is below the PM2_Supporting thresholds defined by the ClinGen Hearing Loss Expert Panel (less than or equal to 0.007%) for autosomal recessive disorders (PM2_Supporting). The computational predictor REVEL gives a score of 0.586 which is neither above nor below the thresholds predicting a damaging or benign impact on USH2A function (no criteria met). It has been reported in the literature in one heterozygous individual with hearing loss; however, a second variant was not identified and there was no reported family history of hearing loss (no criteria met; PMID: 17666888). This variant has been reported by several clinical laboratories in ClinVar as a variant of uncertain significance (ClinVar Variation ID: 447450). Internal laboratory evidence indicates that the variant has been identified in at least three individuals with hearing loss in the heterozygous state without a second GJB2 variant. One individual was reported to have multiple affected relatives; however, segregation data was not available (no criteria met; SCV000613524.1, SCV000731317.1, SCV002817016.1, SCV002179797.2). In summary, this variant is classified as a variant of uncertain significance based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP; PM2_Supporting. The ClinGen Hearing Loss VCEP Specifications Version 2; 09/26/2023.
Athena Diagnostics RCV000516262 SCV000613524 uncertain significance not specified 2016-09-30 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000516262 SCV000731317 uncertain significance not specified 2017-02-28 criteria provided, single submitter clinical testing The p.Val226Gly variant in GJB2 has been reported in the heterozygous state in o ne individual with hearing loss (Putcha 2007). This variant has been identified in 1/11448 Latino chromosomes by the Exome Aggregation Consortium (ExAC, http:// exac.broadinstitute.org; dbSNP rs773846324). Although this variant has been seen in the general population, its frequency is not high enough to rule out a patho genic role. Computational prediction tools and conservation analysis do not prov ide strong support for or against an impact to the protein. In summary, the clin ical significance of the p.Val226Gly variant is uncertain.
Counsyl RCV000664825 SCV000788843 uncertain significance Autosomal recessive nonsyndromic hearing loss 1A 2017-01-04 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV001857902 SCV002179797 uncertain significance not provided 2021-09-24 criteria provided, single submitter clinical testing This sequence change replaces valine with glycine at codon 226 of the GJB2 protein (p.Val226Gly). The valine residue is highly conserved and there is a moderate physicochemical difference between valine and glycine. This variant is present in population databases (rs773846324, ExAC 0.009%). This variant has been observed in individual(s) with deafness (PMID: 20201936; Invitae). ClinVar contains an entry for this variant (Variation ID: 447450). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C15"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Fulgent Genetics, Fulgent Genetics RCV002506252 SCV002817016 uncertain significance 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 2021-10-05 criteria provided, single submitter clinical testing
Natera, Inc. RCV000664825 SCV002094991 uncertain significance Autosomal recessive nonsyndromic hearing loss 1A 2020-08-31 no assertion criteria provided clinical testing

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