ClinVar Miner

Submissions for variant NM_004004.6(GJB2):c.533T>C (p.Val178Ala)

gnomAD frequency: 0.00004  dbSNP: rs568612627
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000665870 SCV000790062 likely pathogenic Autosomal recessive nonsyndromic hearing loss 1A 2017-03-03 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV001218684 SCV001390579 pathogenic not provided 2023-10-14 criteria provided, single submitter clinical testing This sequence change replaces valine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 178 of the GJB2 protein (p.Val178Ala). This variant is present in population databases (rs568612627, gnomAD 0.02%). This missense change has been observed in individuals with autosomal recessive non-syndromic deafness (PMID: 11439000, 21392827, 25189242). ClinVar contains an entry for this variant (Variation ID: 550961). 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. This variant disrupts the p.Val178 amino acid residue in GJB2. Other variant(s) that disrupt this residue have been observed in individuals with GJB2-related conditions (PMID: 28405014), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001779042 SCV002014870 pathogenic Nonsyndromic genetic hearing loss 2021-10-11 criteria provided, single submitter clinical testing Variant summary: GJB2 c.533T>C (p.Val178Ala) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 251290 control chromosomes. c.533T>C has been reported in the literature as a homozygous/compound heterozygous genotype in cohorts of individuals affected with hearing impairment and/or sensorineural hearling loss (SNHL) (example, Hamelmann_2001, Tang_2006, Kabahuma_2011, Neocleous_2014). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic citing overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as pathogenic.
GeneDx RCV001218684 SCV004030610 likely pathogenic not provided 2023-08-25 criteria provided, single submitter clinical testing 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: 25447126, 21392827, 25218342, 18368581, 29140768, 16125251, 25388846, 36048236, 11439000, 25189242, 31620164)
Natera, Inc. RCV000665870 SCV002086039 pathogenic Autosomal recessive nonsyndromic hearing loss 1A 2021-02-08 no assertion criteria provided clinical testing

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