Submissions for variant NM_004004.6(GJB2):c.35G>T (p.Gly12Val)

dbSNP: rs1801002

Total submissions: 19

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000211720	SCV000061504	likely pathogenic	Rare genetic deafness	2012-05-25	criteria provided, single submitter	clinical testing	The Gly12Val variant in GJB2 has been reported in 4 individuals with hearing los s (Kenna 2001, D'Andrea P 2002, Kenna 2010, Rabionet 2000, Snoeckx 2005). At lea st two of these individuals were compound heterozygous. In addition, functional studies suggest that the Gly12Val variant may impact protein function (D'Andrea P 2002). In summary, this data suggests that this variant is likely pathogenic.
Genetic Services Laboratory, University of Chicago	RCV000146020	SCV000193172	pathogenic	Hearing impairment	2013-02-08	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000711351	SCV000227310	pathogenic	not provided	2013-11-05	criteria provided, single submitter	clinical testing
Counsyl	RCV000020570	SCV000487479	likely pathogenic	Autosomal recessive nonsyndromic hearing loss 1A	2016-09-09	criteria provided, single submitter	clinical testing
Counsyl	RCV000412324	SCV000487480	likely pathogenic	Autosomal dominant nonsyndromic hearing loss 3A	2016-09-09	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000711351	SCV000603825	pathogenic	not provided	2020-03-11	criteria provided, single submitter	clinical testing	The GJB2 c.35G>T; p.Gly12Val variant (rs1801002) is a frequently reported pathogenic variant in Hispanic populations (see Purnick 2000, Putcha 2007, Rabionet 2000, Wu 2002). It has been found in a compound heterozygous state with the c.35delG variant and functional studies indicate the p.Gly12Val variant alters GJB2 protein function (D'Andrea 2012). This variant is reported in ClinVar (Variation ID: 21387) and is found in the general population with an overall allele frequency of 0.009% (21/244174 alleles) in the Genome Aggregation Database. Based on available information, we consider this variant to be pathogenic. REFERENCES D'Andrea P et al. Hearing loss: frequency and functional studies of the most common connexin26 alleles. Biochem Biophys Res Commun. 2002 Aug 23;296(3):685-91. Purnick PE et al. Structure of the amino terminus of a gap junction protein. Arch Biochem Biophys. 2000 Sep 15;381(2):181-90. Putcha GV et al. A multicenter study of the frequency and distribution of GJB2 and GJB6 mutations in a large North American cohort. Genet Med. 2007 Jul;9(7):413-26. Rabionet R et al. Molecular basis of childhood deafness resulting from mutations in the GJB2 (connexin 26) gene. Hum Genet. 2000 Jan;106(1):40-4. Wu BL et al. Effectiveness of sequencing connexin 26 (GJB2) in cases of familial or sporadic childhood deafness referred for molecular diagnostic testing. Genet Med. 2002 Jul-Aug;4(4):279-88.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000020570	SCV000698251	pathogenic	Autosomal recessive nonsyndromic hearing loss 1A	2016-06-03	criteria provided, single submitter	clinical testing	Variant summary: The GJB2 c.35G>T (p.Gly12Val) variant involves the alteration of a conserved nucleotide. Gly12 lies in an intracellular domain 1 (IC1) and is a known hot spot codon for recurrent disease-causing mutations. Multiple disease-causing variants are found on this codon: c.35delG (the most common DV), c.35dupG, G12R, G12D, and G12C. 5/5 in silico tools predict a damaging outcome for this variant. This variant was found in 6/119884 control chromosomes at a frequency of 0.00005, which does not exceed the estimated maximal expected allele frequency of a pathogenic GJB2 variant (0.025). This variant has been reported in several nonsyndromic hearing loss patients in the literature in either homozygous or compound homozygous state with other pathogenic variants which is consistent with pathogenic role in recessive module. In addition, according to an in vitro study (DAndrea_2002), Gly12Val substitution causes complete intracellular retention of the connexin and accumulates in large perinuclear vesicles. This dysfunction is accompanied by a significant decrease in its expression, suggesting that G12 is required for the maturation of connexin. Multiple laboratories via ClinVar also classify the variant as pathogenic/likely pathogenic. Considering all evidences, the variant has been classified as pathogenic.
Athena Diagnostics	RCV000711351	SCV000841707	pathogenic	not provided	2017-12-15	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000711351	SCV001237132	pathogenic	not provided	2023-12-14	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 12 of the GJB2 protein (p.Gly12Val). This variant is present in population databases (rs1801002, gnomAD 0.06%). This missense change has been observed in individuals with autosomal recessive non-syndromic deafness (PMID: 10982180, 19371219, 24158611, 25288386). ClinVar contains an entry for this variant (Variation ID: 21387). 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%. Experimental studies have shown that this missense change affects GJB2 function (PMID: 11032405, 12176036, 25625422). For these reasons, this variant has been classified as Pathogenic.
INGEBI, INGEBI / CONICET	RCV001257034	SCV001433539	pathogenic	Nonsyndromic genetic hearing loss	2020-08-21	criteria provided, single submitter	clinical testing	Based on ACMG/AMP guidelines and Hearing Loss Expert Panel specific criteria: the filtering allele frequency of c.35G>T, p.Gly12Val variant is 0,038% (20/34584) of Latino alleles and 0,009% in all populations from gnomAD v2.1.1 database meeting PM2_Supporting criteria. This variant has been found in trans with several pathogenic variants in at least 10 patients with non-syndromic hearing loss among different populations applying to PM3_VerySrong criteria (PMID: 10982180, 11556849, 12172394, 12666888, 19371219, 20233142, 26043044, 26409293, 24158611). Computational analysis predicted the p.Gly12Val change to be damaging to the protein (REVEL=0.95; PP3). Functional studies in HeLa demonstrated that p.Gly12Val mutant was not able to form functional channels since there was a significantly reduce of dye (LuciferYellow) transfer meeting PS3_Moderate rule (PMID:12176036). Therefore, the c.35G>T variant meets criteria to be classified as pathogenic for autosomal recessive non-syndromic hearing loss (PM2_Supporting, PM3_VeryStrong, PP3 and PS3_Moderate).
New York Genome Center	RCV000020570	SCV001480319	pathogenic	Autosomal recessive nonsyndromic hearing loss 1A	2019-09-26	criteria provided, single submitter	clinical testing
GeneDx	RCV000711351	SCV001785322	pathogenic	not provided	2020-03-19	criteria provided, single submitter	clinical testing	Common pathogenic variant in different population groups, predominantly reported in trans with the pathogenic c.35delG variant (Snoeckx et al., 2005); Published functional studies demonstrate this variant causes an intracellular trafficking defect with loss of intercellular transfer and transjunctional conductance (Garcia et al., 2005); Highly conserved residue in the intracellular amino-terminal domain, and variant is predicted to alter the flexibility of this region (Purnick et al., 2000); 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: 33096615, 30275481, 31160754, 16380907, 24158611, 25288386, 26043044, 26444186, 10982180, 11439000, 15365987, 19371219, 19887791, 19929407, 20083784, 20233142, 20668687, 21777984, 21962949, 26409293, 31370293, 25625422, 12176036, 11032405, 12172394, 17666888, 14691997, 11556849, 25388846)
Revvity Omics, Revvity	RCV000711351	SCV002024264	pathogenic	not provided	2021-08-25	criteria provided, single submitter	clinical testing
DASA	RCV000020570	SCV002061257	pathogenic	Autosomal recessive nonsyndromic hearing loss 1A	2022-01-05	criteria provided, single submitter	clinical testing	The c.35G>T;p.(Gly12Val) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 21387; PMID: 20301449; 24158611; 19371219; 10982180; 25288386; 17666888) - PS4. Well-established in vitro or in vivo functional studies support a damaging effect on the gene or gene product (PMID: 12176036, 11032405, 25625422) - PS3. The variant is present at low allele frequencies population databases (rs1801002– gnomAD 0.0002662%; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2_supporting. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV002504816	SCV002810069	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	2022-01-19	criteria provided, single submitter	clinical testing
Laboratory of Medical Genetics, National & Kapodistrian University of Athens	RCV000020570	SCV005051790	pathogenic	Autosomal recessive nonsyndromic hearing loss 1A	2024-02-01	criteria provided, single submitter	curation
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000020570	SCV005399435	pathogenic	Autosomal recessive nonsyndromic hearing loss 1A	2022-02-02	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, 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 autosomal recessive deafness 1A, AR, DD (MIM#220290). Dominant negative is also a suggested mechanism (PMID: 28428247). (I) 0108 - This gene is associated with both recessive and dominant disease. The autosomal dominant diseases are commonly associated with pathogenic missense variants. The autosomal recessive disease is associated with bi-allelic loss-of-function variants and includes missense and protein truncating variants (NIH Genetics Home Reference, PMID: 12792423). (I) 0112 - The condition associated with this gene has incomplete penetrance (PMID:31160754). (I) 0115 - Variants in this gene are known to have variable expressivity. Severity can range from mild to profound with intrafamilial variability also commonly seen. Commonly, truncating variants are associated to a more severe hearing loss (GeneReviews). (I) 0200 - Variant is predicted to result in a missense amino acid change from glycine to valine. (I) 0252 - This variant is homozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2: 23 heterozygotes, 0 homozygotes). (SP) 0309 - Multiple alternative amino acid changes at the same position have been observed in gnomAD (v2) (highest allele count: 127 heterozygotes, 1 homozygote). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is intramembrane (Uniprot), located in the N-terminal region of the annotated connexin domain (DECIPHER, NCBI). (I) 0801 - This variant has very strong previous evidence of pathogenicity in unrelated individuals. It has been classified multiple times as likely pathogenic and pathogenic for biallelic non-syndromic hearing loss and has been shown to have a loss of function effect (ClinVar, GeneReviews, PMID: 29311818). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
GeneReviews	RCV000020570	SCV000041046	not provided	Autosomal recessive nonsyndromic hearing loss 1A		no assertion provided	literature only
PreventionGenetics, part of Exact Sciences	RCV004734527	SCV005352301	pathogenic	GJB2-related disorder	2024-06-14	no assertion criteria provided	clinical testing	The GJB2 c.35G>T variant is predicted to result in the amino acid substitution p.Gly12Val. This variant has been reported in both the compound heterozygous and homozygous state in individuals with non-syndromic hearing loss (Rabionet et al. 2000. PubMed ID: 10982180; Buonfiglio et al. 2020. PubMed ID: 33096615; Figueroa-Ildefonso et al. 2019. PubMed ID: 31370293). A different missense change impacting the same amino acid (c.34G>T, p.Gly12Cys) has been reported in individuals with hearing loss (Internal Data, PreventionGenetics). In vitro functional studies demonstrate reduced protein expression and also showed cellular localization is entirely intracellular (D'Andrea et al. 2002. PubMed ID: 12176036).This variant is reported in 0.058% of alleles in individuals of Latino descent in gnomAD. This variant is interpreted as pathogenic.