ClinVar Miner

Submissions for variant NM_004004.6(GJB2):c.188T>C (p.Val63Ala)

gnomAD frequency: 0.00001  dbSNP: rs727504309
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Total submissions: 8
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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 RCV000154364 SCV000204027 uncertain significance not specified 2014-02-01 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Pathogenic. The Val63Ala va riant in GJB2 has been previously reported in one individual with hearing loss w ho carried a second pathogenic GJB2 variant and was not identified in 588 contro l chromosomes (Tang, 2006). Computational analyses (conservation, AlignGVGD, Pol yPhen2, and SIFT) suggest that the Val63Ala variant may impact the protein, thou gh this information is not predictive enough to determine pathogenicity. In summ ary, the clinical significance of this variant cannot be determined with certain ty; however, based on its presence in an individual with hearing loss who carrie d a second GJB2 variant and the computational and conservation data suggestive o f an impact to the protein, we would lean towards a more likely pathogenic role.
Athena Diagnostics RCV000711348 SCV000841700 uncertain significance not provided 2017-12-20 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV000765115 SCV000896337 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 2018-10-31 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000154364 SCV000917456 uncertain significance not specified 2017-09-11 criteria provided, single submitter clinical testing Variant summary: The GJB2 c.188T>C (p.Val63Ala) variant involves the alteration of a conserved nucleotide. 4/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 5/121934 control chromosomes at a frequency of 0.000041, which does not exceed the estimated maximal expected allele frequency of a pathogenic GJB2 variant (0.025). The variant has been reported in affected individuals in the literature, without evidence for causality. In addition, one clinical diagnostic laboratory classified this variant as uncertain significance. Taken together, this variant is classified as VUS.
GeneDx RCV000711348 SCV001781027 uncertain significance not provided 2022-12-30 criteria provided, single submitter clinical testing Observed with a second GJB2 variant in an individual with hearing loss in published literature, however, the phase of these variants is unknown (Tang et al., 2003); 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: 19366456, 17041943, 25388846, 30245029, 24774219)
Myriad Genetics, Inc. RCV001271875 SCV002060116 uncertain significance Autosomal recessive nonsyndromic hearing loss 1A 2021-10-27 criteria provided, single submitter clinical testing NM_004004.5(GJB2):c.188T>C(V63A) is a missense variant classified as a variant of uncertain significance in the context of GJB2-related DFNB1 nonsyndromic hearing loss and deafness. V63A has been observed in cases with relevant disease (PMID: 17041943, 24774219). Functional assessments of this variant are not available in the literature. V63A has been observed in population frequency databases (gnomAD: AMR 0.03%). In summary, there is insufficient evidence to classify NM_004004.5(GJB2):c.188T>C(V63A) as pathogenic or benign. Please note: this variant was assessed in the context of healthy population screening.
Invitae RCV000711348 SCV002268646 pathogenic not provided 2023-12-28 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 63 of the GJB2 protein (p.Val63Ala). This variant is present in population databases (rs727504309, gnomAD 0.03%). This missense change has been observed in individual(s) with autosomal recessive deafness (PMID: 17041943; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 177751). 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 with a positive predictive value of 95%. This variant disrupts the p.Val63 amino acid residue in GJB2. Other variant(s) that disrupt this residue have been observed in individuals with GJB2-related conditions (PMID: 14985372), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Natera, Inc. RCV001271875 SCV001453348 uncertain significance Autosomal recessive nonsyndromic hearing loss 1A 2020-09-16 no assertion criteria provided clinical testing

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