ClinVar Miner

Submissions for variant NM_004004.6(GJB2):c.134G>A (p.Gly45Glu) (rs72561723)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000022510 SCV000220956 likely pathogenic Deafness, autosomal recessive 1A 2014-12-13 criteria provided, single submitter literature only
Integrated Genetics/Laboratory Corporation of America RCV000022510 SCV001360714 pathogenic Deafness, autosomal recessive 1A 2019-08-21 criteria provided, single submitter clinical testing Variant summary: GJB2 c.134G>A (p.Gly45Glu) results in a non-conservative amino acid change located in the Connexin, N-terminal domain (IPR013092)/first extracellular loop domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 250912 control chromosomes. c.134G>A has been reported as a de-novo variant or as a somatic mosaic in the literature in multiple individuals affected with Keratitis Ichthyosis Deafness Syndrome (KID) (Janecke_2005, Griffith_2006, Jonard_2008, Sbidian_2010, Ogawa_2014, Eskin-Schwartz_2016). These data indicate that the variant is very likely to be associated with disease. Co-occurrence in cis with another pathogenic variant have been reported in the Japanese population (GJB2 c.408C>A, p.Tyr436*), providing supporting evidence for a benign role in the setting of Autosomal Recessive Non-syndromic deafness (Fuse_1999, Ogawa_2014). At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in a complete inability to form functional gap junctions (Rodriguez-Paris_2016). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant when observed in isolation was classified as pathogenic for a phenotype of KID.
OMIM RCV000018561 SCV000038843 pathogenic Keratitis-ichthyosis-deafness syndrome, autosomal dominant 2011-12-01 no assertion criteria provided literature only

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