ClinVar Miner

Submissions for variant NM_004004.6(GJB2):c.487A>G (p.Met163Val) (rs80338949)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000037860 SCV000061522 uncertain significance not specified 2016-05-05 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Pathogenic. The p.Met163Val variant in GJB2 has been identified in >10 probands with non-syndromic hearing loss from several ethnic populations; however, a pathogenic variant on the secon d allele of GJB2 was not detected in any of these probands (Al-Qahtani 2010, Amo rini 2015, Bayazit 2003, Bonyadi 2009, Bonyadi 2014, Chaleshtori 2002, Chaleshto ri 2005, Dalamon 2005, Falah 2012, Gunther 2003, Janecke 2002, Mahdieh 2011, Mar lin 2001, Padma 2009, Tang 2006, Yilmaz 2010). In two families with post-lingual progressive hearing loss described in one study, two parent-to-child segregatio ns were reported for this variant suggesting that the variant may lead to autoso mal dominant hearing loss (Falah 2012). However, the majority of probands in the other studies did not report autosomal dominant inheritance of hearing loss. Tw o other missense variants at the same amino acid position (p.Met163Leu and p.Met 163Thr) have also been reported in individuals with hearing loss, and in vitro f unctional studies of the p.Met163Val and p.Met163Leu show an impact to the norma l activity of the protein due to these variants (Bruzzone 2003, Matos 2008). Thi s data suggests that variants at this amino acid position are not tolerated. The p.Met163Val variant has also been identified 10/16478 South Asian chromosomes b y the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs80338949); however this frequency is not high enough to rule out pathogenicity . In summary, the presence of the p.Met163Val variant in several affected indivi duals and the functional data suggests a pathogenic role for the variant, howeve r the clinical significance of this variant cannot be determined with certainty given the absence of a second pathogenic variant in heterozygous probands and li mited segregation data.
GeneReviews RCV000020573 SCV000041049 pathologic Deafness, autosomal recessive 1A 2011-07-14 no assertion criteria provided curation Converted during submission to Pathogenic.

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