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

gnomAD frequency: 0.00150  dbSNP: rs111033218

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham 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).
Eurofins Ntd Llc (ga)	RCV000037828	SCV000227323	benign	not specified	2015-02-11	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000175768	SCV000383021	likely benign	Autosomal recessive nonsyndromic hearing loss 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 Laboratory Services, Illumina	RCV000274859	SCV000383022	likely benign	Ichthyosis, hystrix-like, with hearing loss	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 Laboratory Services, Illumina	RCV000374467	SCV000383024	likely benign	Autosomal dominant nonsyndromic hearing loss 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.
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000175768	SCV000599739	likely benign	Autosomal recessive nonsyndromic hearing loss 1A	2017-05-09	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000757329	SCV000885512	benign	not provided	2022-09-13	criteria provided, single submitter	clinical testing
GeneDx	RCV000757329	SCV000977443	likely benign	not provided	2020-07-23	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 22995991, 9600457, 26778469, 30828346, 25262649, 20956747, 15070423, 12505163, 24158611, 20981092, 12325027, 25388846, 30245029, 33096615)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000757329	SCV001032575	likely benign	not provided	2024-01-31	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000757329	SCV001143663	likely benign	not provided	2019-02-18	criteria provided, single submitter	clinical testing
INGEBI, INGEBI / CONICET	RCV001257146	SCV001433662	likely benign	Nonsyndromic genetic hearing loss	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).
Fulgent Genetics, Fulgent Genetics	RCV002504896	SCV002808036	likely benign	Autosomal recessive nonsyndromic hearing loss 1A; Mutilating keratoderma; Ichthyosis, hystrix-like, with hearing loss; Autosomal dominant keratitis-ichthyosis-hearing loss syndrome; Palmoplantar keratoderma-deafness syndrome; Knuckle pads, deafness AND leukonychia syndrome; Autosomal dominant nonsyndromic hearing loss 3A; X-linked mixed hearing loss with perilymphatic gusher	2021-11-01	criteria provided, single submitter	clinical testing
Breakthrough Genomics, Breakthrough Genomics	RCV000757329	SCV005219303	likely benign	not provided		criteria provided, single submitter	not provided
Natera, Inc.	RCV000175768	SCV001453870	benign	Autosomal recessive nonsyndromic hearing loss 1A	2020-04-19	no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000757329	SCV001957893	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000757329	SCV001965984	likely benign	not provided		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004534805	SCV004748349	likely benign	GJB2-related disorder	2020-02-28	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).