Submissions for variant NM_004004.6(GJB2):c.200A>G (p.His67Arg)

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Institute of Human Genetics, University of Leipzig Medical Center	RCV003322667	SCV004027649	uncertain significance	Autosomal dominant nonsyndromic hearing loss 3A	2023-05-08	criteria provided, single submitter	clinical testing	Criteria applied: PP3
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003331544	SCV004039534	uncertain significance	not specified	2023-08-15	criteria provided, single submitter	clinical testing	Variant summary: GJB2 c.200A>G (p.His67Arg) results in a non-conservative amino acid change located in the Connexin, N-terminal (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 2.4e-05 in 251358 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.200A>G has been reported in the literature in a heterozygous individual affected with Non-Syndromic Hearing Loss without another variant found (Wu_2002). This report does not provide unequivocal conclusions about association of the variant with Non-Syndromic Hearing Loss. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 12172394). No submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV005103894	SCV005835544	uncertain significance	not provided	2024-09-04	criteria provided, single submitter	clinical testing	This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 67 of the GJB2 protein (p.His67Arg). This variant is present in population databases (rs527914983, gnomAD 0.006%). This missense change has been observed in individual(s) with deafness (PMID: 12172394, 17666888). ClinVar contains an entry for this variant (Variation ID: 2576552). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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.