ClinVar Miner

Submissions for variant NM_004004.6(GJB2):c.457G>A (p.Val153Ile) (rs111033186)

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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000037857 SCV000061519 benign not specified 2015-05-28 criteria provided, single submitter clinical testing p.Val153Ile in exon 2 of GJB2: This variant has been reported in the literature as both a benign polymorphism (Connexins and Deafness Website and other reports) as well as a pathogenic variant (Snoeckx 2005 and other reports). Several repor ts show that this variant occurs at an equal frequency in both hearing loss prob ands and the general population (Guerci 2007, Abidi 2008, RamShankar 2003, Roux 2004, Rickard 2001). It was also identified in 5.6% (922/16488) of South Asian c hromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute .org; dbSNP rs111033186), including 31 homozygous individuals. Functional studie s have demonstrated no impact to synthesis and localization of the connexin 26 p rotein (Guerci 2007). It has also been reported in a homozygous state in 3 indiv iduals with normal hearing (Guerci 2007, RamShankar 2003) as well as identified as a compound heterozygote in a normal hearing individual with the p.Met34Thr mu tation (Malikova 2004). And finally, this variant did not segregate with hearing loss in two kindreds (Gasmelseed 2004, Malikova 2004). In summary, these data s uggest that the p.Val153Ile variant is benign.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000037857 SCV000112274 benign not specified 2012-12-18 criteria provided, single submitter clinical testing
Genetic Services Laboratory,University of Chicago RCV000037857 SCV000193176 benign not specified 2013-02-08 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000037857 SCV000309917 benign not specified criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000270707 SCV000383002 benign Deafness, autosomal dominant 3a 2018-03-06 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Division of Genomic Diagnostics,The Children's Hospital of Philadelphia RCV000505519 SCV000599753 benign Deafness, autosomal recessive 1A 2017-05-09 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000037857 SCV000603811 benign not specified 2018-12-27 criteria provided, single submitter clinical testing
GeneDx RCV000755275 SCV000977441 benign not provided 2018-03-27 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Athena Diagnostics Inc RCV000755275 SCV001143670 likely benign not provided 2018-10-03 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV001109786 SCV001267155 benign Hystrix-like ichthyosis with deafness 2018-03-06 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Illumina Clinical Services Laboratory,Illumina RCV000505519 SCV001267156 likely benign Deafness, autosomal recessive 1A 2018-03-06 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
INGEBI, INGEBI / CONICET RCV001257148 SCV001433664 benign Nonsyndromic hearing loss and deafness 2020-08-31 criteria provided, single submitter clinical testing Based on ACMG/AMP guidelines and Hearing Loss Expert Panel specific criteria: the filtering allele frequency of c.457G>A p.Val153Ile in GJB2 gene is 5% (1642/30610 Southeast Asian chromosomes with 95% CI) from Genome Aggregation Database (http://gnomad.broadinstitute.org; calculated by using inverse allele frequency at https://www.cardiodb.org/allelefrequencyapp/)), which meets the allele frequency threshold defined by the ClinGen Hearing Loss Expert Panel for considering very strong evidence against pathogenicity for autosomal recessive hearing loss variants (BA1). Functional studies demonstrated that mutants lost their abilities to form functional gap junction channels (PMID: 15241677). However, it was shown that there were not differences between p.Val153Ile mutant and wild-type results in dye transfer assay (Guerci V.I, et al 2007). Therefore, functional data was not counted. Besides, the p.Val153Ile change was detected in trans with c.35delG and in homozygous state in normal-hearing individuals applying to BS2 rule (PMID:11493200, 12746422). In summary, this variant meets criteria to be classified as benign for autosomal recessive non-syndromic hearing loss (BA1 and BS2).

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