ClinVar Miner

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

dbSNP: rs111033190
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Total submissions: 8
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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
Invitae 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

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