ClinVar Miner

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

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Total submissions: 13
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000080371 SCV000603834 likely pathogenic not provided 2017-05-03 criteria provided, single submitter clinical testing The p.Gly12Cys variant has been previously reported in multiple hearing loss patients (Azaiez 2004, Putcha 2007, Tang 2006, Hernández-Juárez 2014), but the limited information in the literature is not sufficient to demonstrate causality. However, we have identified two patients in our laboratory who carry p.Gly12Cys on the opposite chromosome from a known pathogenic variant and one patient homozygous for the p.Gly12Cys allele. In addition, two other variants at this same amino acid (p.Gly12Val, p.Gly12Asp) have been previously shown to cause autosomal recessive nonsyndromic hearing loss (Putcha 2007, Ferraris 2002) and one variant (p.Gly12Arg) has been reported in autosomal dominant Keratitis-ichthyosis-deafness syndrome (Neoh 2009). Based on this evidence, we believe that p.Gly12Cys is likely to be pathogenic. References: Azaiez et al.GJB2: the spectrum of deafness-causing allele variants and their phenotype. Hum. Mutat. 2004 24(4):305-11. Ferraris et al. Pyrosequencing for detection of mutations in the connexin 26 (GJB2) and mitochondrial 12S RNA (MTRNR1) genes associated with hereditary hearing loss. Hum Mutat. 2002 20(4):312-320. Hernandez-Juarez 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. Neoh et al. A rare connexin 26 mutation in a patient with a forme fruste of keratitis-ichthyosis-deafness (KID) syndrome. Int J Dermatol. 2009; 48(10):1078-1081. Putcha et al. A multicenter study of the frequency and distribution of GJB2 and GJB6 mutations in a large North American cohort. Genet. Med. 2007 9(7):413-26. Tang et al. 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. 2006 140(22):2401-15.
Athena Diagnostics Inc RCV000080371 SCV000613514 likely pathogenic not provided 2017-07-20 criteria provided, single submitter clinical testing
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.
Clinical Molecular Genetics Laboratory,Johns Hopkins All Children's Hospital RCV000678859 SCV000805052 pathogenic Hearing loss 2017-01-25 no assertion criteria provided clinical testing
Counsyl RCV000410006 SCV000487567 likely pathogenic Deafness, autosomal recessive 1A 2016-04-18 criteria provided, single submitter clinical testing
Counsyl RCV000411497 SCV000487568 likely pathogenic Deafness, autosomal dominant 3a 2016-04-18 criteria provided, single submitter clinical testing
Division of Genomic Diagnostics,The Children's Hospital of Philadelphia RCV000410006 SCV000599722 likely pathogenic Deafness, autosomal recessive 1A 2017-05-09 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000080371 SCV000112268 likely pathogenic not provided 2017-09-28 criteria provided, single submitter clinical testing
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; Keratoderma palmoplantar deafness; Knuckle pads, deafness AND leukonychia syndrome; Deafness, autosomal dominant 3a; Deafness, X-linked 2 2018-10-31 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.
Genetic Services Laboratory, University of Chicago RCV000146017 SCV000193169 pathogenic Hearing impairment 2013-02-08 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000410006 SCV000698247 likely pathogenic Deafness, autosomal recessive 1A 2016-02-09 criteria provided, single submitter clinical testing Variant summary: GJB2 c.34G>T affects a conserved nucleotide, resulting in amino acid change from Gly to Cys. 5/5 in-silico tools predict this variant to be damaging. This variant was found in 52/120462 control chromosomes at a frequency of 0.0004317, which does not significantly exceed maximal expected frequency of a pathogenic GJB2 variant for recessive mode of inheritance (0.025). The variant is present in the control Latino population at a frequency of 0.44%. The relatively high frequency of the variant in the control Latino population excludes the possibility of the variant causing dominantly inherited SNHL. The variant has been detected in at least 2 affected individuals in the homozygous state (1 LabCorp sample, 1 LMM sample [unpublished data]). In addition, this variant has been detected in at least 4 affected individuals with a second pathogenic or likely pathogenic variant detected (internal LabCorp sample, Chan_2010, LMM unpublished data). The variant was also reported in the literature in several other affected individuals as the only known GJB2 variant detected, however in many cases large genomic rearrangements were not tested for, and in some cases the GJB2 gene was not sequenced completely, nor were other hearing loss genes. Two other variants at the same amino acid position have also been reported: c.35G>T/p.Gly12Val is a pathogenic variant associated with autosomal recessive non-syndromic hearing loss, and c.34G>C/p.Gly12Arg has been associated with autosomal dominant Keratitis-ichthyosis-deafness syndrome (in ClinVar; not evaluated by Labcorp yet). In addition, via ClinVar, one clinical laboratory classified this variant as pathogenic, one classified it as likely pathogenic, and another lab classified this variant as VUS, without evidence to independently evaluate. Taken together, this variant is probably a disease variant and is classified as likely pathogenic until more information becomes available.
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.

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