ClinVar Miner

Submissions for variant NM_001110219.3(GJB6):c.263C>T (p.Ala88Val)

dbSNP: rs28937872
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000798432 SCV000938049 pathogenic Autosomal recessive nonsyndromic hearing loss 1A; Autosomal recessive nonsyndromic hearing loss 1B; Autosomal dominant nonsyndromic hearing loss 3B; Hidrotic ectodermal dysplasia syndrome 2024-02-04 criteria provided, single submitter clinical testing This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 88 of the GJB6 protein (p.Ala88Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hidrotic ectodermal dysplasia (also known as Clouston syndrome) (PMID: 11017065, 14708603, 23863883, 27137747). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 5545). 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 not expected to disrupt GJB6 protein function with a negative predictive value of 80%. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on GJB6 function (PMID: 12419304, 15213106, 24522190, 24685692). For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics RCV002504751 SCV002816548 pathogenic Autosomal recessive nonsyndromic hearing loss 1A; Autosomal recessive nonsyndromic hearing loss 1B; Autosomal dominant nonsyndromic hearing loss 3B; X-linked mixed hearing loss with perilymphatic gusher; Hidrotic ectodermal dysplasia syndrome 2022-01-14 criteria provided, single submitter clinical testing
3billion, Medical Genetics RCV000005883 SCV004013533 pathogenic Hidrotic ectodermal dysplasia syndrome criteria provided, single submitter clinical testing The variant is not observed in the gnomAD v2.1.1 dataset.In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.92). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000005545 / PMID: 11017065). The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 10730756, 11017065, 14708603, 17160938, 24052723, 30620052). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
OMIM RCV000005883 SCV000026065 pathogenic Hidrotic ectodermal dysplasia syndrome 2000-10-01 no assertion criteria provided literature only

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