ClinVar Miner

Submissions for variant NM_004004.6(GJB2):c.506G>A (p.Cys169Tyr) (rs774518779)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000256090 SCV000322423 pathogenic not provided 2018-06-25 criteria provided, single submitter clinical testing The C169Y pathogenic variant in the GJB2 gene was initially reported in an individual with hearing loss without a second identifiable variant in this gene; it was not clear from this report whether this individual was heterozygous or homozygous for the C169Y variant (Azaiez et al., 2004). The C169Y variant has subsequently been reported in the homozygous state in multiple individuals from at least three families of Middle Eastern ancestry with hearing loss (Birkenhager et al., 2014; Zonta et al., 2015). In vitro functional analysis demonstrates that the C169Y variant results in disruption of junction channel formation, and disrupts the disulfide bridge that typically forms between the C169 and C64 residues (Zonta et al., 2015). The C169Y variant is observed in 2/111440 (0.003%) alleles from individuals of non-Finnish European background in large population cohorts (Lek et al., 2016). The C169Y variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. We interpret C169Y as a pathogenic variant.
Integrated Genetics/Laboratory Corporation of America RCV000587164 SCV000698263 pathogenic Deafness, autosomal recessive 1A 2017-06-20 criteria provided, single submitter clinical testing Variant summary: The GJB2 c.506G>A (p.Cys169Tyr) variant involves the alteration of a conserved nucleotide. "Cys169 is one of the six extracellular cysteine residues which are conserved in all connexin isoforms. These six cysteines form three disulfide bridges, which are likely to play an important role in guiding the correct folding of the connexin protein and the docking of the two hexameric hemichannels in the extracellular region" via Zonta_2015. 4/4 in silico tools predict a damaging outcome. A functional study, Zonta_2015 supports these predictions and showed that the variant "At the cellular level, our results show that the mutant protein fails to form junctional channels in HeLa transfectants despite being correctly targeted to the plasma membrane. At the molecular level, this effect can be accounted for by disruption of the disulfide bridge that Cys169 forms with Cys64 in the wild-type structure (Cx26WT)." This variant was found in 2/121012 control chromosomes at a frequency of 0.0000165, which does not exceed the estimated maximal expected allele frequency of a pathogenic GJB2 variant (0.025). Multiple publications have cited the variant in homozygous affected individuals, in addition a heterozygous affected individual, which a second mutation was not indicated to have been found. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Fulgent Genetics,Fulgent Genetics RCV000763322 SCV000893999 pathogenic Deafness, autosomal recessive 1A; Mutilating keratoderma; Hystrix-like ichthyosis with deafness; Keratitis-ichthyosis-deafness syndrome, autosomal dominant; Keratoderma palmoplantar deafness; Knuckle pads, deafness AND leukonychia syndrome; Deafness, autosomal dominant 3a; Deafness, X-linked 2 2018-10-31 criteria provided, single submitter clinical testing

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