Submissions for variant NM_004004.6(GJB2):c.104T>G (p.Ile35Ser)

gnomAD frequency: 0.00001  dbSNP: rs756467247

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV001544685	SCV001763860	likely pathogenic	not provided	2020-12-07	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 26186295, 11587277, 23504403, 16380907, 18941476, 29921236, 24840842, 25388846)
Invitae	RCV001544685	SCV002228265	pathogenic	not provided	2024-01-22	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 35 of the GJB2 protein (p.Ile35Ser). This variant is present in population databases (rs756467247, gnomAD 0.006%). This missense change has been observed in individual(s) with autosomal recessive non-syndromic deafness (PMID: 11587277, 24840842). 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: 1185804). 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: 18941476). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003331179	SCV004037709	pathogenic	Nonsyndromic genetic hearing loss	2023-08-29	criteria provided, single submitter	clinical testing	Variant summary: GJB2 c.104T>G (p.Ile35Ser) results in a non-conservative amino acid change located in the Connexin, N-terminal (IPR013092) of 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 8e-06 in 250806 control chromosomes. c.104T>G has been reported in the literature in multiple individuals affected with Non-Syndromic Hearing Loss (e.g. Mani_2009, Dahl_2001, Bukhari_2013). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function demonstrated that this variant results in impaired trafficking to the plasma membrane (Mani_2009). The following publications have been ascertained in the context of this evaluation (PMID: 23504403, 11587277, 18941476, 17666888). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.