ClinVar Miner

Submissions for variant NM_004004.6(GJB2):c.249C>G (p.Phe83Leu) (rs111033218)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000037828 SCV000061490 benign not specified 2012-06-26 criteria provided, single submitter clinical testing Phe83Leu in exon 2 of GJB2: This variant is not expected to have clinical signif icance because it has been identified in 0.3% (28/8572) of European American chr omosomes and 0.07% (3/4403) of African American chromosomes from a broad populat ion by the NHLBI Exome sequencing project (http://evs.gs.washington.edu/EVS/; db SNP rs111033218). In addition, this has been observed at equal frequencies in af fected individuals and controls (Scott 1998, Heathcote 2000, Prasad 2000, Rabion et 2000, Pandya 2003, Bruzzone 2003, Frei 2004, Roux 2004, Sinnathuray 2004, Che ng 2005, Santos 2005, Frei 2006, Tang 2006, Ramsebner 2007, Ross 2007, Picotti 2 009, Lee 2009, Kimani 2010). Furthermore, functional studies revealed that the v ariant protein behaves similar to that of the wild type protein (Bruzzone 2003).
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000037828 SCV000227323 benign not specified 2015-02-11 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000175768 SCV000383021 likely benign Deafness, autosomal recessive 1A 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Illumina Clinical Services Laboratory,Illumina RCV000274859 SCV000383022 likely benign Hystrix-like ichthyosis with deafness 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Illumina Clinical Services Laboratory,Illumina RCV000374467 SCV000383024 likely benign Deafness, autosomal dominant 3a 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Division of Genomic Diagnostics,The Children's Hospital of Philadelphia RCV000175768 SCV000599739 likely benign Deafness, autosomal recessive 1A 2017-05-09 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000037828 SCV000885512 benign not specified 2019-03-07 criteria provided, single submitter clinical testing
GeneDx RCV000757329 SCV000977443 likely benign not provided 2018-03-23 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.
Invitae RCV000757329 SCV001032575 likely benign not provided 2019-12-31 criteria provided, single submitter clinical testing
Athena Diagnostics Inc RCV000757329 SCV001143663 likely benign not provided 2019-02-18 criteria provided, single submitter clinical testing
INGEBI, INGEBI / CONICET RCV001257146 SCV001433662 likely 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.249C>G variant (p.Phe83Leu) in GJB2 gene is 0,28% (404/ 29116 European non-Finnish 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 supporting evidence against pathogenicity for autosomal recessive hearing loss variants (BS1_Supporting). The p.Phe83Leu change has been identified in trans with a pathogenic dominant variant in a family case with KID syndrome applying to BP2 rule (PMID: 10633135). Functional studies demonstrated that p.Phe83Leu mutant generated electrical conductance like the wild type in Xenopus laevis oocytes. Besides, 100% of dye transfer was detected in HeLa cells expressing p.Phe83Leu mutant (PMID:12505163). Hence, this evidence meets BS3_Sup standard. Therefore, this variant meets criteria to be classified as likely benign for autosomal recessive non-syndromic hearing loss: (BS1_Supporting, BP2 and BS3_Supporting).

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