Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV003062565 | SCV003442022 | pathogenic | not provided | 2022-08-13 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects GJB2 function (PMID: 18941476). 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. This missense change has been observed in individuals with autosomal recessive deafness (PMID: 18941476, 25388846, 33614373). This variant is present in population databases (rs575453513, gnomAD 0.006%). This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 33 of the GJB2 protein (p.Ile33Thr). |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV004690348 | SCV005185157 | pathogenic | Nonsyndromic genetic hearing loss | 2024-05-21 | criteria provided, single submitter | clinical testing | Variant summary: GJB2 c.98T>C (p.Ile33Thr) results in a non-conservative amino acid change located in the Connexin, N-terminal domain (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 1.2e-05 in 250622 control chromosomes. c.98T>C has been reported in the literature the homozygous state in multiple individuals affected with autosomal recessive Non-Syndromic Hearing Loss (example, Hedge_2021, Mani_2009). These data indicate that the variant is very likely to be associated with disease. In vitro evaluations of this variant in HeLa cells found reduced protein levels (~25% of controls) and abolished dye transfer capabilities, suggesting defective gap junction channel activity (example, Mani_2009). The following publications have been ascertained in the context of this evaluation (PMID: 33614373, 18941476). ClinVar contains an entry for this variant (Variation ID: 2137461). Based on the evidence outlined above, the variant was classified as pathogenic. |
| Fulgent Genetics, |
RCV005010899 | SCV005632119 | likely pathogenic | 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 | 2024-05-23 | criteria provided, single submitter | clinical testing |