Submissions for variant NM_004004.6(GJB2):c.299A>T (p.His100Leu)

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Total submissions: 2

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Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000781416	SCV000919429	likely pathogenic	Autosomal recessive nonsyndromic hearing loss 1A	2018-08-02	criteria provided, single submitter	clinical testing	Variant summary: GJB2 c.299A>T (p.His100Leu) results in a non-conservative amino acid change located in the Connexin, N-terminal domain (IPR013092) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.2e-05 in 31172 control chromosomes (gnomAD and publication data). The variant, c.299A>T, has been reported in the literature in individuals affected with Non-Syndromic Hearing Loss (Primignani 2009, Du 2014). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity (Kim 2016). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Invitae	RCV001873191	SCV002261740	likely pathogenic	not provided	2023-12-01	criteria provided, single submitter	clinical testing	This sequence change replaces histidine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 100 of the GJB2 protein (p.His100Leu). This variant is present in population databases (no rsID available, gnomAD 0.01%). This missense change has been observed in individual(s) with autosomal recessive deafness (PMID: 19371219, 24256046). ClinVar contains an entry for this variant (Variation ID: 633242). 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%. Experimental studies have shown that this missense change affects GJB2 function (PMID: 26749107). This variant disrupts the p.His100 amino acid residue in GJB2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11102979, 16467727, 20553101, 21287563, 26749107). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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