Submissions for variant NM_004004.6(GJB2):c.34G>T (p.Gly12Cys)

gnomAD frequency: 0.00009  dbSNP: rs104894408

Total submissions: 20

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Hearing Loss Variant Curation Expert Panel	RCV000037839	SCV000840536	likely pathogenic	Nonsyndromic genetic hearing loss	2022-10-19	reviewed by expert panel	curation	The c.34G>T (NM_004004.6) in GJB2 is a missense variant predicted to cause the substitution of glycine by cysteine at amino acid 12 (p.Gly12Cys). The highest population minor allele frequency in gnomAD v2.1.1 is 0.0036 (128/35104 alleles) in the Latino/Admixed American population, which is higher than the ClinGen Hearing Loss VCEP threshold (>0.003) for BS1, and therefore meets this criterion (BS1). This is a high enough frequency that, in absence of conflicting data, might warrant a likely benign classification based on the thresholds defined by the ClinGen Hearing Loss VCEP for autosomal recessive hearing loss variants. However, based on the evidence outlined below, the ClinGen Hearing Loss Expert Panel believes that the evidence for the pathogenicity of this variant for nonsyndromic hearing loss outweighs its high allele frequency in population databases. Therefore, the BS1 code will not contribute to the overall classification. This variant has been detected in at least 10 patients with hearing loss. Of those individuals, at least 4 were compound heterozygous or the variant and a pathogenic or likely pathogenic variant was observed in trans and one proband was homozygous for the variant (c.35delG, p.V37I, p.Val198fs, p.Lys122Ile, PMID: 15365987, 17041943, 17666888, 25288386, 26969326, 31035178, SCV000061501.5) (PM3_Very Strong). A different pathogenic missense variant (p.Gly12Val) (ClinVar Variation ID 21387) in the same codon of GJB2 has been classified as likely pathogenic and pathogenic for hearing loss by 7 labs who are in concordance that this variant is LP/P (PM5). The computational predictor REVEL gives a score of 0.838, and the nucleotide is heavily conserved in UCSC, which is above the threshold of 0.7, evidence that correlates with impact to GJB2 function (PP3). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal recessive nonsyndromic genetic hearing loss based on the ACMG/AMP criteria applied as specified by the Hearing Loss VCEP: PM3_Very Strong, PM5, PP3, BS1 (ClinGen Hearing Loss VCEP specifications version 2; 10/19/2022)
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000844703	SCV000061501	likely pathogenic	Rare genetic deafness	2018-11-28	criteria provided, single submitter	clinical testing	The p.Gly12Cys variant in GJB2 has been previously identified by our laboratory in 7 individuals with hearing loss; one individual was homozygous for the varian t and four individuals had a second pathogenic or likely pathogenic variant in G JB2, supporting an autosomal recessive inheritance pattern. The p.Gly12Cys varia nt has also been reported in the literature in 11 individuals with hearing loss. In 1 individual, a variant affecting the remaining copy of GJB2 was identified; however, in the remaining 10 individuals, a variant affecting the remaining DFN B1 allele was not identified (Tang 2006, Azaiez 2004, Putcha 2007, Mendelsberg-F ishbein 2013, Hernandez-Juarez 2014). Furthermore, this variant has been reporte d in ClinVar and is classified as likely pathogenic by the Hearing Loss Expert P anel (ClinVar Variation ID 44740). This variant was identified in 0.38% (129/340 98) of Latino chromosomes by the Genome Aggregation Database (gnomAD, http://gno mad.broadinstitute.org; dbSNPrs104894408). While the frequency data meets the th reshold for likely benign variants when there is no conflicting information, the evidence supporting pathogenicity outweighs the evidence supporting a likely be nign classification. Three other amino acid changes have been reported at this p osition; p.Gly12Arg has been associated with clinical features of an autosomal d ominant form of hearing loss (Keratitis-Ichthyosis-deafness syndrome), and p.Gly 12Val and p.Gly12Asp which have been associated with an autosomal recessive hear ing loss. Glycine (Gly) at position 12 is highly conserved in mammals and evolut ionarily distant species, supporting that a change at this position may not be t olerated. Additional computational prediction tools suggest that the p.Gly12Cys variant may impact the protein. In summary, although additional studies are requ ired to fully establish its clinical significance, this variant meets criteria t o be classified as likely pathogenic for autosomal recessive hearing loss. ACMG/ AMP Criteria applied: PM3_VeryStrong, PM5, PP3.
Eurofins Ntd Llc (ga)	RCV000080371	SCV000112268	likely pathogenic	not provided	2017-09-28	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000146017	SCV000193169	pathogenic	Hearing impairment	2013-02-08	criteria provided, single submitter	clinical testing
GeneDx	RCV000080371	SCV000321724	pathogenic	not provided	2021-12-15	criteria provided, single submitter	clinical testing	Reported in published literature in the heterozygous state in multiple unrelated individuals with congenital hearing loss (Azaiez et al., 2004; Tang et al., 2006; Hernndez-Jurez et al. 2014); Observed in two heterozygous individuals who reported a family history suggestive of autosomal dominant hearing loss, but no segregation studies were performed for the p.(G12C) variant (Tang et al., 2006; Sloan-Heggen et al., 2016); 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: 25262649, 17666888, 25388846, 26969326, 26444186, 15365987, 25288386, 18987669, 26252218, 11912510, 22643125, 22011219, 31163360, 31160754, 30275481, 20154630, 17041943)
Counsyl	RCV000411497	SCV000487568	likely pathogenic	Autosomal dominant nonsyndromic hearing loss 3A	2016-04-18	criteria provided, single submitter	clinical testing
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000410006	SCV000599722	likely pathogenic	Autosomal recessive nonsyndromic hearing loss 1A	2017-05-09	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000080371	SCV000603834	likely pathogenic	not provided	2021-07-30	criteria provided, single submitter	clinical testing	The c.34G>T p.Gly12Cys variant (rs104894408) is reported in the literature in multiple hearing loss patients (Putcha 2007, Tang 2006, Hernandez-Juarez 2014, Shen 2019). Testing performed at ARUP Laboratories has identified two individuals with hearing loss who carry p.Gly12Cys on the opposite chromosome from a known pathogenic GJB2 variant and a third affected individual homozygous for the p.Gly12Cys variant. In addition, two other variants at this same amino acid (p.Gly12Val, p.Gly12Asp) have been reported in individuals with autosomal recessive nonsyndromic hearing loss and are considered pathogenic (Putcha 2007, Hernandez-Juarez 2014). The glycine at codon 12 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL:0.838). Based on available evidence, the p.Gly12Cys variant is considered to be likely pathogenic. References: Hernandez-Juarez AA et al. GJB2 and GJB6 mutations are an infrequent cause of autosomal-recessive nonsyndromic hearing loss in residents of Mexico. Int J Pediatr Otorhinolaryngol. 2014 Dec;78(12):2107-2012. Putcha et al. 2007. A multicenter study of the frequency and distribution of GJB2 and GJB6 mutations in a large North American cohort. Genet. Med. 9(7):413-26. Tang et al. 2006. DNA sequence analysis of GJB2, encoding connexin 26: observations from a population of hearing impaired cases and variable carrier rates, complex genotypes, and ethnic stratification of alleles among controls. Am. J. Med. Genet. A. 140(22):2401-15. Shen J et al. ClinGen Hearing Loss Working Group. Consensus interpretation of the p.Met34Thr and p.Val37Ile variants in GJB2 by the ClinGen Hearing Loss Expert Panel. Genet Med. 2019 Nov;21(11):2442-2452. PMID: 31160754.
Athena Diagnostics	RCV000080371	SCV000613514	likely pathogenic	not provided	2021-09-09	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been identified in at least one individual with clinical features associated with this gene. At least one other missense variant at this codon is considered to be pathogenic or likely pathogenic, suggesting this variant may also cause disease. In multiple individuals, this variant has been seen with a single recessive pathogenic variant in the same gene, suggesting this variant may also be pathogenic. Computational tools predict that this variant is damaging.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000410006	SCV000698247	likely pathogenic	Autosomal recessive nonsyndromic hearing loss 1A	2023-12-13	criteria provided, single submitter	clinical testing	Variant summary: GJB2 c.34G>T (p.Gly12Cys) results in a non-conservative amino acid change located in the N-terminal domain (IPR013092) 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 0.00051 in 247086 control chromosomes, predominantly at a frequency of 0.0036 within the Latino subpopulation in the gnomAD database, including 1 homozygote. This frequency is not higher than the estimated maximum expected for a pathogenic variant in GJB2 causing Autosomal Recessive Non-Syndromic Hearing Loss, allowing no conclusion about variant significance. However, the relatively high frequency of the variant suggests that it is unlikely to be associated with dominantly inherited non-syndromic hearing loss. The variant, c.34G>T, has been reported in the literature in compound heterozygous state together with other (likely) pathogenic variants in GJB2 in individuals affected with Non-Syndromic Hearing Loss (e.g. Chan_2010, Jiang_2015, Wu_2017 (NO_PMID), Shen_2019, Florentine_2022). In addition, the variant has also been reported in an individual affected with hearing loss who carried a likely pathogenic deletion in GJB6, suggesting that the variant may have contributed to hearing loss by a digenic mechanism in this patient (Raymond_2019). These data indicate that the variant is likely to be associated with disease. Although the variant has been reported in (apparent) heterozygosity in multiple individuals in whom a second mutation was not identified (e.g. Azaiez_2004, Tang_2006, Putcha_2007, Hernandez-Juarez_2014, Jiang_2015, Tayoun_2015, Xiang_2019), however in many of these cases, the GJB2 gene was not completely sequenced, other hearing loss-associated genes were not tested, and/or large rearrangements were not assessed; thus these reports do not provide conclusive evidence for causality. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. However, other variants at the same amino acid position (G12V/R/D) have been reported in affected individuals (HGMD), and c.35G>T (p.Gly12Val) has been classified as a pathogenic by our laboratory for autosomal recessive non-syndromic hearing loss. The following publications have been ascertained in the context of this evaluation (PMIDs: 15365987, 20154630, 31099403, 25288386, 32090102, 26252218, 17666888, 31163360, 31160754, 26969326, 17041943, 26444186, 31035178, 34515852). 15 other submitters (including an expert panel) have provided clinical-significance assessments for this variant in ClinVar after 2014 and classified the variant as pathogenic (n=3) / likely pathogenic (n=11; including the expert panel), or likely benign (n=1). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV000762906	SCV000893316	likely 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	2022-01-14	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000080371	SCV001095617	likely pathogenic	not provided	2024-01-21	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with cysteine, which is neutral and slightly polar, at codon 12 of the GJB2 protein (p.Gly12Cys). This variant is present in population databases (rs104894408, gnomAD 0.4%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with autosomal recessive nonsyndromic sensorineural deafness (PMID: 20154630, 26969326, 31163360; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 44740). 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%. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Baylor Genetics	RCV001004399	SCV001163371	likely pathogenic	Autosomal recessive nonsyndromic hearing loss 1A; Autosomal recessive nonsyndromic hearing loss 1B		criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000410006	SCV001523118	likely pathogenic	Autosomal recessive nonsyndromic hearing loss 1A	2020-05-04	criteria provided, single submitter	clinical testing	This variant was determined to be likely pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
Mendelics	RCV002247424	SCV002516480	pathogenic	Mutilating keratoderma	2022-05-04	criteria provided, single submitter	clinical testing
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV003224797	SCV003920883	likely 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	2021-03-30	criteria provided, single submitter	clinical testing	GJB2 NM_004004.5 p.Gly12Cys (c.34G>T): This variant has been reported in the literature in at least 6 individuals with hearing loss (Azaiez 2004 PMID: 15365987, Tang 2006 PMID:17041943, Putcha 2007 PMID:17666888, Hernandez-Juarez 2014 PMID:25288386, Raymond 2019 PMID:31163360). On of these patients showed digenic inheritance with a pathogenic deletion of GJB6. However, at least 2 of these individuals did not have an additional disease causing variant identified, and the zygosity of this variant for the other individuals is unclear. This variant is present in 0.3% (129/34098) of Latino alleles, including 1 homozygote in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs104894408). This variant is present in ClinVar, with several labs classifying this variant as likely pathogenic or pathogenic (Variation ID: 44740). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. In summary, data on this variant is highly suspicious for disease, but requires further evidence for pathogenicity. Therefore, this variant classified as likely pathogenic.
Integrating Genomics into Medicine, Frazer Institute, University Of Queensland	RCV000410006	SCV003935276	likely pathogenic	Autosomal recessive nonsyndromic hearing loss 1A	2023-06-02	criteria provided, single submitter	clinical testing
Counsyl	RCV000410006	SCV000487567	likely pathogenic	Autosomal recessive nonsyndromic hearing loss 1A	2016-04-18	no assertion criteria provided	clinical testing
Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital	RCV000678859	SCV000805052	pathogenic	Hearing loss	2017-01-25	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004734553	SCV005350445	likely pathogenic	GJB2-related disorder	2024-08-23	no assertion criteria provided	clinical testing	The GJB2 c.34G>T variant is predicted to result in the amino acid substitution p.Gly12Cys. This variant has been reported in the literature along with a second GJB2 variant in at least three individuals with hearing loss (Chan et al. 2010. PubMed ID: 20154630; Jiang et al. 2015. PubMed ID: 26252218; Supplemental File 2, Florentine et al. 2022. PubMed ID: 34515852) as well as one patient undergoing testing for hearing loss at PreventionGenetics. It has also been reported in the heterozygous state in the absence of a second potentially causative variant in patients with hearing loss, although the completeness of testing the GJB2 gene and upstream regulatory elements as well as other hearing loss related genes in these individuals is unknown (Azaiez et al. 2004. PubMed ID: 15365987; Tang et al. 2006. PubMed ID: 17041943; Putcha et al. 2007. PubMed ID: 17666888). This variant is reported in 0.36% of alleles in individuals of Latino descent in gnomAD, including 1 homozygote. In ClinVar this variant is classified as likely pathogenic by the ClinGen Hearing Loss Variant Curation Expert Panel for autosomal recessive hearing loss, citing internal data from another laboratory in which this variant was observed in the homozygous state or in trans with a second causative variant in five affected individuals (https://www.ncbi.nlm.nih.gov/clinvar/variation/44740/). Another substitution at this amino acid position (p.Gly12Val) has also been reported in individuals with hearing loss (Chan et al. 2010. PubMed ID: 20154630; Rabionet et al. 2000. PubMed ID: 10982180; Figueroa-Ildefonso et al. 2019. PubMed ID: 31370293), and a different substitution (p.Gly12Arg) has been reported in individuals with keratitis-ichthyosis-deafness syndrome (Richard et al. 2002. PubMed ID: 11912510), indicating this position is important for normal protein function. While the clinical significance of this variant is uncertain for autosomal dominant disorders, this variant is interpreted as likely pathogenic for autosomal recessive hearing loss.