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

Total submissions: 12

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).