ClinVar Miner

Submissions for variant NM_004004.6(GJB2):c.380G>A (p.Arg127His) (rs111033196)

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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 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.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000037847 SCV000112273 benign not specified 2012-12-18 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000037847 SCV000309916 likely benign not specified criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000325483 SCV000383003 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 RCV000505535 SCV000599749 benign Deafness, autosomal recessive 1A 2017-05-09 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000037847 SCV000603832 benign not specified 2018-08-09 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America 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 Clinical Services Laboratory,Illumina RCV001109789 SCV001267159 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 RCV000505535 SCV001268028 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 RCV001257158 SCV001433676 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 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.

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