ClinVar Miner

Submissions for variant NM_004004.6(GJB2):c.487A>C (p.Met163Leu) (rs80338949)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
INGEBI, INGEBI / CONICET RCV001251627 SCV001427361 uncertain significance Nonsyndromic hearing loss and deafness 2020-08-04 criteria provided, single submitter clinical testing Based on ACMG/AMP guidelines and Hearing Loss Expert Panel (HL-EP) specific criteria: the c.487A>C, p.Met163Leu variant in GJB2 gene is absent from population databases (gnomAD, GO-ESP, 1000 genomes) meeting PM2 criteria. Computational evidence is not enough to meet neither PP3 nor BP4 rules, since REVEL score is 0.534. This variant has been detected in a family case in the proband and her affected mother. In the same report, the variant was studied in HeLa cells demonstrating that the mutant protein p.Met163Leu had defective trafficking to the plasma membrane and was associated with increased cell death (PMID:18472371). Since the functional studies performed in that report were not the specified by the HL-EP, the evidence strength has been downgraded to PS3_Supporting. Besides, the p.Met163Leu change has beed identified in heterozygous state in two hearing loss patients (PMID: 23668481;19887791) meeting PS4_Supporting rule. In summary, the clinical significance of this variant is currently uncertain (PM2, PS3_Supporting, PS4_Supporting).
GeneReviews RCV000487480 SCV000574688 pathogenic Deafness, autosomal dominant 3a 2016-12-22 no assertion criteria provided literature only

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