ClinVar Miner

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

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 8
Download table as spreadsheet
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,; 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.
CeGaT Praxis fuer Humangenetik Tuebingen RCV001092709 SCV001249345 uncertain significance not provided 2019-12-01 criteria provided, single submitter clinical testing
INGEBI, INGEBI / CONICET RCV001257048 SCV001433599 uncertain significance 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 filtering allele frequency of c.487A>G, p.Met163Val variant in GJB2 gene is 0,05% (23/30604 South Asian alleles with 95%CI) from Genome Aggregation Database (; calculated by using inverse allele frequency at which meets the criteria to apply to PM2_Supporting rule. Computational evidence predicted a pathogenic effect of the mutation to the protein (REVELscore: 0.869) applying to PP3 criteria. The p.Met163Val change has been identified only in heterozygous state in several patients (PMID: 11493200, 14643477, 15964725, 12189487, 12872268). Besides, in two familial cases this variant segregate in two affected individuals and their affected fathers (PMID:22208444). So, this evidence is not enough to be counted. On the other hand, p.Met163Val change was identified in homozygous state in a control subject meeting BS2 rule (PMID: 20086291). Functional studies demonstrated a highly reduction of dye transfer of p.Met163Val mutant in HeLa cells (PMID:28428247). Besides, it was shown that this mutant was unable to form functional gap junction channels in Xenopus Laevis oocytes (PMID:12505163). Hence, PS3_Moderate criteria was applied. In summary, the clinical significance of this variant is currently uncertain (PM2_Supporting, PP3, PS3_Moderate, BS2).
Department of Otolaryngology – Head & Neck Surgery, Cochlear Implant Center RCV001375209 SCV001571911 likely pathogenic Hearing impairment 2021-04-12 criteria provided, single submitter clinical testing PS1_Strong, PM2_Moderate, PM5_Moderate, PP3_Supporting
GeneDx RCV001092709 SCV001784037 uncertain significance not provided 2020-03-05 criteria provided, single submitter clinical testing Observed in the heterozygous state with no other GJB2 variant in multiple individuals with hearing loss in published literature (Hamid et al., 2009; Al-Qahtani et al., 2010; Janecke et al., 2002; Marlin et al., 2001); Observed in unaffected parents of children with hearing loss who were heterozygous for the variant in published literature (Bonyadi et al., 2009; Leone et al., 2017); Published functional studies demonstrate a damaging effect on gap junction function (Press et al., 2017; Bruzzone et al., 2003); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 33096615, 31412945, 31620696, 12872268, 17041943, 16380907, 20086306, 19715472, 30989077, 15964725, 19929407, 28263784, 22695344, 19941053, 21388256, 26096904, 14643477, 21996152, 28428247, 25388846, 12189487, 11493200, 24158611, 22208444, 12505163, 20086291, 24529908, 31569309)
Nilou-Genome Lab RCV000020573 SCV001810444 uncertain significance Deafness, autosomal recessive 1A 2021-07-22 criteria provided, single submitter clinical testing
Nilou-Genome Lab RCV001787816 SCV002029256 uncertain significance Deafness, autosomal dominant 3a 2021-09-05 criteria provided, single submitter clinical testing
GeneReviews RCV000020573 SCV000041049 pathologic Deafness, autosomal recessive 1A 2011-07-14 no assertion criteria provided curation Converted during submission to Pathogenic.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.