ClinVar Miner

Submissions for variant NM_004004.6(GJB2):c.408C>A (p.Tyr136Ter)

gnomAD frequency: 0.00001  dbSNP: rs786204690
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000169498 SCV000220957 likely pathogenic Autosomal recessive nonsyndromic hearing loss 1A 2014-12-13 criteria provided, single submitter literature only
Invitae RCV001850402 SCV002246427 pathogenic not provided 2023-11-28 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Tyr136*) in the GJB2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 91 amino acid(s) of the GJB2 protein. This variant is present in population databases (rs786204690, gnomAD 0.003%). This premature translational stop signal has been observed in individuals with autosomal recessive non-syndromic deafness. While this variant is commonly found in cis with p.Gly45Glu, it has also been observed without p.Gly45Glu in affected individuals and is expected to be causative for autosomal recessive non-syndromic deafness whether p.Gly45Glu is present or not (PMID: 10501520, 10607953, 20497192, 21112098). ClinVar contains an entry for this variant (Variation ID: 189092). This variant disrupts a region of the GJB2 protein in which other variant(s) (p.Leu213*) have been determined to be pathogenic (PMID: 23141775). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV001850402 SCV002577218 pathogenic not provided 2022-03-28 criteria provided, single submitter clinical testing Commonly found in cis with p.(G45E) which is associated with autosomal dominant KID syndrome when seen alone; p.(Y136*) is associated with autosomal recessive nonsyndromic hearing loss whether alone or with p.(G45E) on the same allele (Ogawa et al., 2014; Rodriguez-Paris et al., 2016); Identified on the same allele (in cis) with p.(G45E), either in the homozygous state or with a pathogenic variant on the opposite allele, in multiple unrelated patients with sensorineural hearing loss in the literature (Fuse et al., 1999; Tsukada et al., 2010; Hayashi et al., 2011); Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 91 amino acids are lost, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (HGMD); Published functional studies demonstrate a loss of function due to failure of the variant protein to form gap junctions, but with no effect on wild-type gap junctions; when present in cis with p.(G45E), the dominant negative effect of p.(G45E) on gap junction formation is neutralized (Rodriguez-Paris et al., 2016); This variant is associated with the following publications: (PMID: 26763877, 31160754, 18941476, 17666888, 12560944, 27792752, 29605341, 25587757, 26668150, 24785414, 10501520, 21112098, 10607953, 10633133, 27761313, 20497192)

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