ClinVar Miner

Submissions for variant NM_004004.6(GJB2):c.109G>A (p.Val37Ile) (rs72474224)

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Total submissions: 19
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Hearing Loss Variant Curation Expert Panel, RCV000211759 SCV000927014 pathogenic Nonsyndromic hearing loss and deafness 2019-06-24 reviewed by expert panel curation The filtering allele frequency (the lower threshold of the 95% CI of 143/1558, including 8 homozygous observations) of the c.109G>A (p.Val37Ile) variant in the GJB2 gene is 7.9% for East Asian genomes in gnomAD.This is a high enough frequency that, in the absence of conflicting data, might warrant a benign classification based on the thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss variants (BA1). 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 BA1 code will not contribute to the overall classification. The homozygous genotype and compound heterozygous genotype with another variant in GJB2 have shown to be statistically enriched in patients with nonsyndromic sensorineural hearing loss compared to individuals representative of the general population in gnomAD and/or those who underwent carrier screening at Counsyl. (PS4; PMID: 31160754). This study also reported the variant in 139 homozygous affected probands, 17 affected probands with the p.Met34Thr variant in trans, 131 affected probands with a variant asserted to be P/LP in ClinVar, and 78 affected probands with a premature GJB2 termination codon in trans. However, because the variant is also very frequent in the general population, this criteria has been applied at the strength of Moderate. (PM3; PMID: 31160754). The p.Val37Ile variant in GJB2 has been reported to segregate with hearing loss in at least 21 family members (PP1_Strong; PMID: 31160754). Although homozygous or compound heterozygous observations have been identified in individuals with normal hearing, it has been suggested that individuals with the p.Val37Ile variant lose hearing at ~1dB/year, suggesting an age-related penetrance (PMID: 27308859). Furthermore, in dye transfer and electrical coupling assays, both functional studies have shown that the variant impacts protein function (PMID: 26088551, 12505163, 16300957) and knock-in mouse model demonstrated that the p.Val37Ile variant leads to the phenotype. However, because the codon for p.Val37 in mouse (GTG) was different from that in human (GTT), c.109G>A in mouse would translate into p.Val37Met, and the dye transfer and coupling assays have limited validation and correlation with pathogenicity, neither was not counted as functional evidence. (PMID: 27623246). Of note, the severity of hearing loss is known to be mild on average and there have been multiple accounts of incomplete penetrance of the variant in families/individuals with p.Val37Ile in a biallelic genotype. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive nonsyndromic genetic hearing loss based on the ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: PS4, PP1_Strong, PM3.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000844700 SCV000061474 pathogenic Rare genetic deafness 2011-01-24 criteria provided, single submitter clinical testing The p.Val37Ile variant in GJB2 is known to be pathogenic and, in homozygosity or when combined with another GJB2 variant, typically results in a mild to moderat e hearing loss (Snoeckx 2005, Huculak 2006, Pollak 2007) or in rare cases, may e ven be associated with normal hearing. ACMG/AMP Criteria applied: PS4, PP1_Stro ng, PM3_VeryStrong.
Genetic Services Laboratory, University of Chicago RCV000146005 SCV000193156 pathogenic Hearing impairment 2013-02-08 criteria provided, single submitter clinical testing
UCLA Clinical Genomics Center, UCLA RCV000018550 SCV000255378 likely pathogenic Deafness, autosomal recessive 1A 2013-10-01 criteria provided, single submitter clinical testing
GeneDx RCV000080365 SCV000322430 pathogenic not provided 2018-10-10 criteria provided, single submitter clinical testing The V37I variant in the GJB2 gene has been reported frequently in association with autosomal recessive nonsyndromic sensorineural hearing loss (NSHL) of mild severity compared to other reported pathogenic variants in the GJB2 gene (Snoeckx et al., 2005; Tang et al., 2006). However, V37I is a common GJB2 variant in the Asian population, and has been observed in 1546/18868 alleles (7.2%), from individuals of East Asian background in the ExAC dataset, including 88 unaffected homozygous individuals (Gallanet et al., 2013; Lek et al., 2016). The prevalence and presence of homozygous individuals in control populations suggests that V37I shows reduced penetrance. This variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position in the conserved transmembrane domain of connexin 26. Functional studies show V37I significantly reduces calcium-induced biochemical permeability of the connexin 26, but does not impose significant additional effects in gap junction function (Kim et al., 2015). Missense variants at the same codon (V37L and V37A) have been reported in association with hearing loss, supporting the functional importance of this residue (Azaiez et al., 2004; Putcha et al., 2007). Based on the available information, we consider V37I to be a pathogenic variant. This variant is associated with a range of hearing loss severity from asymptomatic to profound, but predominantly results in milder hearing loss.
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV000146005 SCV000492740 likely pathogenic Hearing impairment 2014-05-21 criteria provided, single submitter clinical testing
Division of Genomic Diagnostics,The Children's Hospital of Philadelphia RCV000018550 SCV000599730 uncertain significance Deafness, autosomal recessive 1A 2017-05-09 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000080365 SCV000603818 pathogenic not provided 2017-05-26 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000515287 SCV000611199 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 2017-05-18 criteria provided, single submitter clinical testing
Athena Diagnostics Inc RCV000080365 SCV000613504 pathogenic not provided 2016-02-26 criteria provided, single submitter clinical testing
Counsyl RCV000018550 SCV000678021 pathogenic Deafness, autosomal recessive 1A 2015-10-28 criteria provided, single submitter clinical testing V37I is associated with a variable presentation, ranging from clinically asymptomatic to severe hearing loss.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000080365 SCV000700275 pathogenic not provided 2016-08-17 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000018550 SCV000915626 pathogenic Deafness, autosomal recessive 1A 2017-04-27 criteria provided, single submitter clinical testing The GJB2 c.109G>A (p.Val37Ile) missense variant is widely reported in the literature. The variant was first identified in a compound heterozygous state with a second variant in a single individual with hearing loss (Abe et al. 2000). Pollak et al. (2007) found the variant was significantly overrepresented in individuals with hearing loss as compared to controls (5.2% compared to 0.43%) and suggested that this variant might cause a late onset, mild form of hearing loss with reduced penetrance when found in combination with other variants in the GJB2 gene. In an evaluation of over 1000 newborns, Wu et al. (2011) identified several homozygotes and compound heterozygotes for the p.Val37Ile variant, with both normal hearing and varying degrees of hearing loss. Expression studies have demonstrated that the p.Val37Ile variant results in a complete loss of homotypic gap junction channel activity (Snoeckx et al. 2005). The p.Val37Ile variant is reported at a frequency of 0.08586 in the Kinh in Ho Chi Minh City, Vietnam, population of the 1000 Genomes Project. This frequency is high but may be consistent with the prevalence of mild hearing loss in the population. Based on the collective evidence, the p.Val37Ile variant is classified as pathogenic for autosomal recessive nonsyndromic hearing loss, though is associated with a mild phenotype and reduced penetrance. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Integrated Genetics/Laboratory Corporation of America RCV000018550 SCV000919432 pathogenic Deafness, autosomal recessive 1A 2018-10-15 criteria provided, single submitter clinical testing Variant summary: GJB2 c.109G>A (p.Val37Ile) results in a conservative amino acid change located in the Connexin, N-terminal of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0074 in 280234 control chromosomes in the gnomAD database, including 91 homozygotes. This frequency is not significantly higher than expected for a pathogenic variant in GJB2 causing Autosomal Recessive Non-Syndromic Hearing Loss (0.0074 vs 0.025), allowing no conclusion about variant significance. This variant was first listed as a polymorphism by Kelley_1998 due to finding of one heterozygote of this variant in 96 control persons. However, all following studies on genotype-phenotype in patients and gene function suggest that this variant is pathogenic. In hearing loss patients with this variant, clinical severity ranges from mild to moderate. In a Chinese study (Chai_2015), the variant was strongly associated with both mild-to-moderate (p=2.01011) and severe-to-profound (p=0.001) HI, but was estimated to have a rather low penetrance (17%). Huang_2015 showed that among the 3,864 Chinese patients, 106 (2.74%) had a homozygous p.V37I variation or a compound p.V37I plus other GJB2 pathogenic mutation, a frequency that was significantly higher than that in the control group (600 individuals, 0%). Homozygotes of this variant or compound heterozygotes of this variant and a pathogenic variant in GJB2 were reported in patients with hearing loss in populations other than East Asian (Robionet_2000, Wilcox_2000, Snoeckx_2005). In vitro junctional conductance and biochemical permeability study on mutant Cx26 V37I showed the function of Cx26 V37I was significantly decreased (Bruzzone_2003 and Kim_2015). Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Eight of these have reported a classification as pathogenic (n=7) or likely pathogenic (n =1). This is consistent with the results of the "Clingen hearing loss variant curation expert panel" that has settled upon a classification for this variant as "Pathogenic" based on compelling statistical and supporting functional evidence (personal correspondence, manuscript in preparation at this time of classification) . Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae RCV000080365 SCV000957235 pathogenic not provided 2019-01-06 criteria provided, single submitter clinical testing This sequence change replaces valine with isoleucine at codon 37 of the GJB2 protein (p.Val37Ile). The valine residue is highly conserved and there is a small physicochemical difference between valine and isoleucine. This variant is present in population databases (rs72474224, ExAC 7%). This variant has been reported in the literature in a large meta-analysis involving several thousand cases and controls (PMID: 28489599). This variant has been reported frequently in individuals affected with mild to moderate hearing loss particularly among populations in eastern Asia (PMID: 23637863, 26885124, 26061099, 17036313, 16952406, 21488715), and has been shown to segregate with hearing loss in families (PMID: 28489599, 24945352, 26088551). Although this variant is more common in the population than expected for a pathogenic variant, the penetrance of this variant is estimated to be less than 20% of other disease-causing variants in GJB2 (PMID: 17935238, 24654934). ClinVar contains an entry for this variant (Variation ID: 17023). Experimental studies have shown that this missense change disrupts the formation of homotypic junctional channels in vitro (PMID: 12505163). Furthermore in vivo knock-in and knock-out mouse models recapitulate the hearing loss phenotype observed in humans (PMID: 27623246). In summary, this variant is reported to cause sensorineural hearing loss. However, as this variant is associated with a lower penetrance than other pathogenic alleles in the GJB2 gene, it has been classified as Pathogenic (low penetrance).
OMIM RCV000018550 SCV000038832 pathogenic Deafness, autosomal recessive 1A 2007-11-01 no assertion criteria provided literature only
GeneReviews RCV000018550 SCV000041039 pathologic Deafness, autosomal recessive 1A 2011-07-14 no assertion criteria provided curation Converted during submission to Pathogenic.
Division of Human Genetics,Children's Hospital of Philadelphia RCV000018550 SCV000238418 pathogenic Deafness, autosomal recessive 1A 2015-01-23 no assertion criteria provided research This patient is a carrier of a heterozygous pathogenic variant in the GJB2 gene associated with autosomal recessive deafness 1A. The GJB2 variant (c.109G>A; p.V37I) identified in this patient is a missense variant reported to be a common pathogenic variant in individuals with Asian ancestry and is associated with mild to moderate, sometimes progressive hearing impairment in individuals with various ages. (Gallant et al. 2013, PMID: 23873582; Huculak et al. 2006, PMID: 17036313; Bruzzone et al. 2003, PMID: 12505163; Li et al. 2012, PMID: 22574200)
Genetic Testing Center for Deafness, Department of Otolaryngology Head & Neck Surgery,Institute of Otolaryngology, Chinese PLA General Hospital RCV000018550 SCV000902313 likely pathogenic Deafness, autosomal recessive 1A 2019-02-26 no assertion criteria provided case-control

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