ClinVar Miner

Submissions for variant NM_001110219.3(GJB6):c.301G>C (p.Glu101Gln)

dbSNP: rs571454176
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000821653 SCV000962422 uncertain significance Autosomal recessive nonsyndromic hearing loss 1A; Autosomal recessive nonsyndromic hearing loss 1B; Autosomal dominant nonsyndromic hearing loss 3B; Hidrotic ectodermal dysplasia syndrome 2018-08-17 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with glutamine at codon 101 of the GJB6 protein (p.Glu101Gln). The glutamic acid residue is moderately conserved and there is a small physicochemical difference between glutamic acid and glutamine. This variant is present in population databases (rs571454176, ExAC 0.02%). 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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with GJB6-related disease.
Neuberg Centre For Genomic Medicine, NCGM RCV003338823 SCV004048258 uncertain significance Autosomal dominant nonsyndromic hearing loss 3B criteria provided, single submitter clinical testing The missense variant c.301G>C (p.Glu101Gln) in GJB6 gene has been submitted to ClinVar as a Variant of Uncertain Significance, but no details are available for independent assessment. It has not been reported in affected individuals. The p.Glu101Gln variant is reported with the allele frequency (0.005%) in the gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. The amino acid Glu at position 101 is changed to a Gln changing protein sequence and it might alter its composition and physico-chemical properties. In silico tools predict the variant to be tolerated. The residue is conserved across species. The amino acid change p.Glu101Gln in GJB6 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Variant of Uncertain Significance (VUS).

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