ClinVar Miner

Submissions for variant NM_004004.6(GJB2):c.389G>C (p.Gly130Ala)

dbSNP: rs779018464
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000213896 SCV000271227 likely pathogenic Rare genetic deafness 2017-09-19 criteria provided, single submitter clinical testing The p.Gly130Ala variant in GJB2 has been previously reported in 6 individuals wi th hearing loss, three of whom were compound heterozygous for a second pathogeni c variant in GJB2 (Chora 2010, Hwa 2003, Chaleshtori 2005, Primignani 2009, Riah i 2013). This variant has not been identified in large population studies. Two different variants at the same amino acid position, p.Gly130Val (Iossa 2009, Sn oeckx 2005) and p.Gly130Asp (Putcha 2007), have also been reported in individual s with hearing loss, with the p.Gly130Val variant reported to cause dominant hea ring loss and palmoplantar keratoderma. Computational prediction tools and conse rvation analyses suggest that the p.Gly130Ala variant may impact the protein, th ough this information alone is not predictive enough to determine pathogenicity. In summary, although additional studies are required to fully establish its cli nical significance, this variant is likely pathogenic. ACMG/AMP Criteria applie d: PM3_S, PM2, PP3 (Richards 2015).
Counsyl RCV000411886 SCV000487448 likely pathogenic Autosomal recessive nonsyndromic hearing loss 1A 2015-12-11 criteria provided, single submitter clinical testing
Counsyl RCV000409464 SCV000487449 likely pathogenic Autosomal dominant nonsyndromic hearing loss 3A 2015-12-11 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV001853423 SCV002134486 uncertain significance not provided 2023-09-11 criteria provided, single submitter clinical testing This sequence change replaces glycine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 130 of the GJB2 protein (p.Gly130Ala). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with features of both autosomal dominant and autosomal recessive deafness (PMID: 12792423, 19371219, 20650534, 23680645, 31160754). ClinVar contains an entry for this variant (Variation ID: 228264). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt GJB2 protein function. 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.
Natera, Inc. RCV000411886 SCV002086049 likely pathogenic Autosomal recessive nonsyndromic hearing loss 1A 2021-08-15 no assertion criteria provided clinical testing

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