ClinVar Miner

Submissions for variant NM_004004.6(GJB2):c.503A>G (p.Lys168Arg) (rs200104362)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000037859 SCV000061521 likely benign not specified 2011-12-12 criteria provided, single submitter clinical testing Lys168Arg in exon 2 of GJB2: This variant has been reported in 8/567 (1.4%) Hisp anic probands and 14/3832 (0.3%) control individuals (Christiani 2007, Batissoco 2009, Samanich 2007, Tsukada 2010). The frequency of the variant in controls an d the fact that none of the probands had a second variant identified on the othe r copy of the gene suggests that the variant is more likely benign.
Division of Genomic Diagnostics,The Children's Hospital of Philadelphia RCV000505507 SCV000599755 uncertain significance Deafness, autosomal recessive 1A 2017-05-09 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000590717 SCV000698262 likely benign not provided 2016-06-09 criteria provided, single submitter clinical testing Variant summary: The GJB2 c.503A>G (p.Lys168Arg) variant involves the alteration of a conserved nucleotide, however, arginine is in the same basic amino acid group as lysine. 3/4 in silico tools predict a benign outcome (SNPs&GO not captured due to low reliability index). This variant was found in 10/122334 control chromosomes, predominantly observed in the Latino subpopulations at a frequency of 0.00061 (7/11532). This frequency is about 2 times the estimated maximal expected allele frequency of a pathogenic GJB2 variant (0.0003376), suggesting this is likely a benign polymorphism found primarily in the populations of Latino origin. This variant has been reported in affected individuals without strong evidence for causality, and most reported patients whom carry this variant are from South America (Hispanic). In addition, one other reputable clinical diagnostic laboratory classified this variant as likely benign. Taken together, this variant is classified as probably benign until additional information becomes available.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000590717 SCV000858602 uncertain significance not provided 2017-12-12 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000590717 SCV000885518 uncertain significance not provided 2017-12-29 criteria provided, single submitter clinical testing The GJB2 p.Lys168Arg variant (rs200104362) has been reported in multiple people who were part of hearing loss cohorts; however, inheritance and specific clinical information were not provided for these individuals (selected references: Batissoco 2009, Manzoli 2013, Samanich 2007, Shearer 2014). The p.Lys168Arg variant is listed in the Genome Aggregation Database (gnomAD) browser with an overall allele frequency of 0.0061% (identified in 17 out of 276,848 chromosomes), and is found in the ClinVar database (Variant ID: 44756). The lysine at codon 168 is highly conserved considering 10 species up to dog (Alamut software v2.10.0), but computational analyses predict that this variant does not affect the structure/function of the GJB2 protein (SIFT: tolerated, PolyPhen2: benign, Align GVGD: C0). Based on the available information, the clinical significance of the p.Lys168Arg variant cannot be determined with certainty.

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