Submissions for variant NM_004004.6(GJB2):c.380G>A (p.Arg127His)

gnomAD frequency: 0.00143  dbSNP: rs111033196

Total submissions: 18

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000037847	SCV000061509	benign	not specified	2013-04-24	criteria provided, single submitter	clinical testing	This variant is not expected to have clinical significance. Although there is so me controversy in the literature over the significance of this variant, after a thorough review of the following papers (Estivill et al. 1998; Marlin et al. 200 1; D'Andrea et al. 2002; Thonnissen et al. 2002; RamShankar et al, 2003; Wang et al. 2003; Toth et al, 2004; Chaleshtori et al. 2006; Dahl et al, 2006; Palmada et al, 2006) we conclude that the Arg127His variant is not causative for hearing loss. This conclusion is mainly due to its common (17.5%) occurrence in an Asia n Indian control population (RamShankar et al, 2003) and homozygous and compound heterozygous identification in individuals with normal hearing (Marlin et al. 2 001; RamShankar et al, 2003; Dahl et al, 2006). In addition, it has been reporte d in two large population studies; the Arg127His variant has been identified in has been identified in 0.3% (26/8600) of European American chromosomes by the NH LBI Exome Sequencing Project and 0.23% (5/2178) chromosomes by the 1000 Genomes Project (http://evs.gs.washington.edu/EVS/; dbSNP rs111033196). In summary, this variant is meets our criteria to be classified as benign due to its high freque ncy in the general population and its presence in the homozygous state in unaffe cted individuals.
Eurofins Ntd Llc (ga)	RCV000037847	SCV000112273	benign	not specified	2012-12-18	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000037847	SCV000309916	likely benign	not specified		criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000325483	SCV000383003	benign	Autosomal dominant nonsyndromic hearing loss 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.
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000505535	SCV000599749	benign	Autosomal recessive nonsyndromic hearing loss 1A	2017-05-09	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000589067	SCV000603832	benign	not provided	2023-04-06	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000589067	SCV000698244	benign	not provided	2017-08-08	criteria provided, single submitter	clinical testing
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000626854	SCV000747557	uncertain significance	Progressive sensorineural hearing impairment	2017-01-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000589067	SCV000977442	benign	not provided	2018-06-08	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.
Illumina Laboratory Services, Illumina	RCV001109789	SCV001267159	benign	Ichthyosis, hystrix-like, with hearing loss	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 Laboratory Services, Illumina	RCV000505535	SCV001268028	likely benign	Autosomal recessive nonsyndromic hearing loss 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	RCV001257158	SCV001433676	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 filter allele frequency of c.380G>A, p.Arg127His variant in GJB2 gene is 9.5% (3021/30612 South 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 threshold to apply for BA1 rule. Computational evidence was not enough to neither apply to PP3 nor BP4 since REVEL score was 0.387. This variant has been identified in trans with pathogenic variants in control subjects meeting BS2 rule (PMID: 11493200, 15070423, 12746422). It was shown in some familial cases that different genotypes composed of p.Arg127His change in homozygous state and in compound heterozygous with pathogenic variants did not segregate within the members of those families applying to BS4 criteria (PMID:19929408). On the other hand, this variant has been detected in trans with pathogenic variants in at least for patients with hearing loss (PMID: 16380907, 12746422, 19366456, 19929408). However, since this genetic variant presents a high allele frequency in general population, the PM3 rule was downgraded to supporting strength (PM3_Supporting). Functional studies (dye transfer assay and electrophysiological records) in HeLa cells and Xenopus Laevis oocytes presented contradictory results, so that evidence was not counted (PMID: 12176036, 16300957, 12189493, 12562518). In summary, this variant meets criteria to be classified as benign for autosomal recessive non-syndromic hearing loss: BA1, BS2, BS4, PM3_Supporting.
Athena Diagnostics Inc	RCV000037847	SCV001476378	benign	not specified	2020-08-27	criteria provided, single submitter	clinical testing
Invitae	RCV000589067	SCV001720414	benign	not provided	2024-02-01	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000505535	SCV001463372	benign	Autosomal recessive nonsyndromic hearing loss 1A	2020-09-16	no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000037847	SCV001807908	benign	not specified		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000589067	SCV001957712	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000037847	SCV001966867	benign	not specified		no assertion criteria provided	clinical testing