Submissions for variant NM_004004.6(GJB2):c.194A>G (p.Tyr65Cys)

gnomAD frequency: 0.00002  dbSNP: rs111033203

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV001731333	SCV001983160	uncertain significance	not provided	2025-01-15	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25388846, 26444186, 36048236, 31160754, 34308104, 38486023)
Integrating Genomics into Medicine, Frazer Institute, University Of Queensland	RCV001826561	SCV003935278	likely pathogenic	Autosomal recessive nonsyndromic hearing loss 1A	2023-06-02	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004526604	SCV005039020	uncertain significance	not specified	2024-03-27	criteria provided, single submitter	clinical testing	Variant summary: GJB2 c.194A>G (p.Tyr65Cys) 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 251324 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.194A>G has been reported in the literature in individuals affected with Non-Syndromic Hearing Loss (Shen_2019, Tayoun_2015). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 31160754, 26444186, 36048236). ClinVar contains an entry for this variant (Variation ID: 44727). Based on the evidence outlined above, the variant was classified as uncertain significance.
Fulgent Genetics, Fulgent Genetics	RCV005007953	SCV005634676	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	2024-04-02	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001731333	SCV005836135	uncertain significance	not provided	2024-06-30	criteria provided, single submitter	clinical testing	This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 65 of the GJB2 protein (p.Tyr65Cys). This variant is present in population databases (rs111033203, gnomAD 0.005%). This missense change has been observed in individual(s) with GJB2-related conditions (PMID: 26444186, 31160754). ClinVar contains an entry for this variant (Variation ID: 44727). 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%. 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.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000037819	SCV000061481	likely pathogenic	Rare genetic deafness	2006-10-28	no assertion criteria provided	clinical testing
Natera, Inc.	RCV001826561	SCV002086062	likely pathogenic	Autosomal recessive nonsyndromic hearing loss 1A	2021-03-11	no assertion criteria provided	clinical testing