Submissions for variant NM_004004.6(GJB2):c.598G>A (p.Gly200Arg)

dbSNP: rs786204597

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000210857	SCV000487490	likely pathogenic	Autosomal recessive nonsyndromic hearing loss 1A	2016-01-21	criteria provided, single submitter	clinical testing
Counsyl	RCV000411925	SCV000487491	likely pathogenic	Autosomal dominant nonsyndromic hearing loss 3A	2016-01-21	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001853379	SCV002231530	pathogenic	not provided	2023-08-08	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 200 of the GJB2 protein (p.Gly200Arg). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects GJB2 function (PMID: 23967136). 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. ClinVar contains an entry for this variant (Variation ID: 225222). This missense change has been observed in individuals with autosomal recessive deafness (PMID: 21094084, 24949729). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000210857	SCV002511671	pathogenic	Autosomal recessive nonsyndromic hearing loss 1A	2022-04-08	criteria provided, single submitter	clinical testing	Variant summary: GJB2 c.598G>A (p.Gly200Arg) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251254 control chromosomes. c.598G>A has been reported in the literature as homozygous and compound heterozygous genotypes in multiple individuals from diverse ethnicities affected with Autosomal Recessive Non-Syndromic Hearing Loss (example, Liu_2009, Bliznets_2012, Chaleshtori_2005, Shafique_2014, Bakhchane_2016). 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 demonstrating improper trafficking with intracellular aggregation (Ambrosi_2013). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000210857	SCV005398663	pathogenic	Autosomal recessive nonsyndromic hearing loss 1A	2022-02-02	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.3, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with both deafness (MIM#220290, #601544) and diseases affecting skin (various MIM#s). Dominant negative is also a potential mechanism of disease (PMID: 28428247). (I) 0108 - This gene is associated with both recessive and dominant disease. Autosomal dominant disease is associated with pathogenic missense variants, while autosomal recessive disease is associated with biallelic loss-of-function variants including missense and protein truncating variants (PMID: 11179004, 12792423). (I) 0112 - The condition associated with this gene has incomplete penetrance (PMID:31160754). (I) 0200 - Variant is predicted to result in a missense amino acid change from glycine to arginine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported in multiple individuals with autosomal recessive hearing loss in the homozygous or compound heterozygous state (ClinVar, PMID: 22695344, 24949729, 27169813, 31992338). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Cell line studies demonstrated that this variant results in abnormal protein trafficking (PMID: 23967136). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Institut Pasteur du Maroc	RCV000210857	SCV000267104	pathogenic	Autosomal recessive nonsyndromic hearing loss 1A	2016-04-01	no assertion criteria provided	clinical testing	Pathogenic