ClinVar Miner

Submissions for variant NM_004004.6(GJB2):c.34G>T (p.Gly12Cys) (rs104894408)

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Total submissions: 16
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Hearing Loss Variant Curation Expert Panel RCV000037839 SCV000840536 likely pathogenic Nonsyndromic hearing loss and deafness 2018-09-11 reviewed by expert panel curation The filtering allele frequency of the p.Gly12Cys variant in the GJB2 gene is 0.32% (129/34098) of Latino chromosomes by the Genome Aggregation Database (http://gnomad.broadinstitute.org; calculated by using inverse allele frequency at https://www.cardiodb.org/allelefrequencyapp/). 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 Expert Panel for autosomal recessive hearing loss variants (BS1). However, based on the evidence outline 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 patients with hearing loss in trans with at least 4 pathogenic or suspected-pathogenic variants (PM3_VS; Partners LMM internal data SCV000061501.5). The p.Gly12Cys variant has also been reported in the literature in 10 individuals with hearing loss; however, a variant affecting the remaining DFNB1 allele was not reported (PMID: 15365987, 17041943, 17666888, 25288386, 26969326). A different pathogenic missense variant (p.Gly12Val) has been previously identified at this codon of GJB2 which may indicate that this residue is critical to the function of the protein (PM5; ClinVar Variation ID 21387). Computational prediction tools and conservation analysis suggest that the p.Gly12Cys variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as likely pathogenic for autosomal recessive nonsyndromic hearing loss based on the ACMG/AMP criteria applied as specified by the Hearing Loss Expert Panel: PM3_VS, PM5, PP3, BS1.
Laboratory for Molecular Medicine, Partners HealthCare 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.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics 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 likely pathogenic not provided 2018-06-22 criteria provided, single submitter clinical testing The G12C variant in the GJB2 gene has been reported in the heterozygous and compound heterozygous states in multiple unrelated individuals with congenital hearing loss (Azaiez et al., 2004; Tang et al., 2006; Chan et al., 2010; Hernández-Juárez et al. 2014; Sloan-Heggen et al., 2016). Two individuals who were found to harbor the G12C variant reported a family history of hearing loss suggestive of autosomal dominant inheritance; however, no segregation studies were performed for the G12C variant (Tang et al., 2006; Sloan-Heggen et al., 2016). The variant is observed in 129/34098 (0.378%) alleles from individuals of Latino background in large population cohorts (Lek et al., 2016). G12C is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. In addition, missense variants at this residue (G12R/D/V) and in nearby residues (T8M/T, L10P, G11E, V13M) have been reported in the Human Gene Mutation Database in association with GJB2-related disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein. In summary, we consider this variant to be likely pathogenic; however, the possibility it may be a rare benign variant cannot be excluded.
Counsyl RCV000411497 SCV000487568 likely pathogenic Deafness, autosomal dominant 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 Deafness, autosomal recessive 1A 2017-05-09 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000999736 SCV000603834 likely pathogenic not specified 2019-02-02 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). 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). 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.
Athena Diagnostics Inc RCV000080371 SCV000613514 likely pathogenic not provided 2017-07-20 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000410006 SCV000698247 likely pathogenic Deafness, autosomal recessive 1A 2020-09-02 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 (no known clinical or audiometric evaluation data for this individual). This frequency is lower than the estimated maximum frequency expected for a pathogenic variant in GJB2 causing Autosomal Recessive Non-Syndromic Hearing Loss (0.0036 vs 0.025), allowing no conclusion about variant significance for recessive hearing loss. However, the relatively high frequency of the variant in the Latino population suggests that it is unlikely that this variant would be associated with dominantly inherited Non-Syndromic Hearing Loss. c.34G>T has been reported in the literature in compound heterozygosity with other pathogenic/ likely pathogenic variants in GJB2 in individuals affected Non-Syndromic Hearing Loss (examples- Chan_2010, Shen_2019). In addition, the variant has 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 recessively-inherited disease. Several other publications cite the variant in compound heterozygosity with other pathogenic variants in GJB2 in individuals affected with hearing loss, but classify the variant as a polymorphism (evidence for this classification not provided; examples- Jiang_2015, Wu_2017). The variant has also been detected in a heterozygous state in multiple individuals in whom a second mutation was not identified (examples- Azaiez_2004, Tang_2006, Putcha_2007, Mendelburg-Fishbein_2013, Hernandez-Juarez_2014, Jiang_2015, Tayoun_2015, Xiang_2019). In many of these cases, however, 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 and no co-segregation studies evaluating the variant in multiple affected family members have been reported in the literature. Other variants at the same amino acid position have been reported as associated with disease: c.35G>T; p.Gly12Val has been classified as a pathogenic mutation associated with autosomal recessive non-syndromic hearing loss, c.34G>C; p.Gly12Arg has been reported in the literature to be associated with autosomal dominant Keratitis-ichthyosis-deafness syndrome (Lazik_2012, Neoh_2009), and c.35G>A; p. Gly12Asp has been reported in at least one publication to be associated with hereditary hearing loss (Ferraris_2002). 11 other ClinVar submitters (evaluation after 2014) have cited the variant with conflicting assessments: 10 (including one expert panel) classified the variant as pathogenic/likely pathogenic, 1 classified the variant as likely benign. Based on the evidence outlined above, until additional information becomes available, the variant was classified as likely pathogenic.
Fulgent Genetics,Fulgent Genetics RCV000762906 SCV000893316 likely pathogenic Deafness, autosomal recessive 1A; Mutilating keratoderma; Hystrix-like ichthyosis with deafness; Keratitis-ichthyosis-deafness syndrome, autosomal dominant; Palmoplantar keratoderma-deafness syndrome; Knuckle pads, deafness AND leukonychia syndrome; Deafness, autosomal dominant 3a; Deafness, X-linked 2 2018-10-31 criteria provided, single submitter clinical testing
Invitae RCV000080371 SCV001095617 likely benign not provided 2020-12-02 criteria provided, single submitter clinical testing
Baylor Genetics RCV001004399 SCV001163371 likely pathogenic Deafness, autosomal recessive 1A; Deafness, autosomal recessive 1b criteria provided, single submitter clinical testing
Baylor Genetics RCV000410006 SCV001523118 likely pathogenic Deafness, autosomal recessive 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].
Counsyl RCV000410006 SCV000487567 likely pathogenic Deafness, autosomal recessive 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

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