Submissions for variant NM_004004.6(GJB2):c.95G>T (p.Arg32Leu)

dbSNP: rs111033190

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000727027	SCV000705030	likely pathogenic	not provided	2017-02-06	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000727027	SCV001212469	pathogenic	not provided	2024-01-07	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 32 of the GJB2 protein (p.Arg32Leu). This variant is present in population databases (rs111033190, gnomAD 0.02%). This missense change has been observed in individuals with autosomal recessive non-syndromic deafness (PMID: 19157576, 20154630, 22925408). ClinVar contains an entry for this variant (Variation ID: 499513). 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%. This variant disrupts the p.Arg32 amino acid residue in GJB2. Other variant(s) that disrupt this residue have been observed in individuals with GJB2-related conditions (PMID: 11493200), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000727027	SCV001780838	likely pathogenic	not provided	2023-10-03	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Identified in patients with hearing loss in published literature (PMID: 12172394, 19157576, 25085072); This variant is associated with the following publications: (PMID: 25388846, 21112098, 24840842, 26186295, 29542069, 20154630, 22925408, 25085072, 19157576, 12172394)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002232559	SCV002511669	pathogenic	Nonsyndromic genetic hearing loss	2022-04-21	criteria provided, single submitter	clinical testing	Variant summary: GJB2 c.95G>T (p.Arg32Leu) results in a non-conservative amino acid change located in the first transmembrane domain (Joseph_2009) 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 3.2e-05 in 250526 control chromosomes. c.95G>T has been reported in the literature as homozygous and compound heterozygous genotypes in individuals affected with Non-Syndromic Hearing Loss (example, Wu_2002, Yamuna Joseph_2009, Chan_2010, de la Luz Arenas-Sordo_2012). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four 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.
Fulgent Genetics, Fulgent Genetics	RCV002476305	SCV002784027	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; X-linked mixed hearing loss with perilymphatic gusher	2021-08-06	criteria provided, single submitter	clinical testing
Counsyl	RCV000597784	SCV000790085	likely pathogenic	Autosomal recessive nonsyndromic hearing loss 1A	2017-03-06	no assertion criteria provided	clinical testing
Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital	RCV000678865	SCV000805058	likely pathogenic	Hearing loss	2014-04-22	no assertion criteria provided	clinical testing
Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals	RCV002232559	SCV002754541	pathogenic	Nonsyndromic genetic hearing loss	2022-05-11	no assertion criteria provided	clinical testing