ClinVar Miner

Submissions for variant NM_022124.6(CDH23):c.3764A>T (p.Lys1255Met) (rs372158876)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000489371 SCV000577106 uncertain significance not provided 2017-04-11 criteria provided, single submitter clinical testing The K1255M variant in the CDH23 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The K1255M variant is observed in 19/16366 (0.11%) alleles from individuals of South Asian background in the ExAC dataset (Lek et al., 2016). The K1255M 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. This substitution occurs at a position that is conserved across species. However, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We interpret K1255M as a variant of uncertain significance.
Invitae RCV000489371 SCV001209667 uncertain significance not provided 2020-01-08 criteria provided, single submitter clinical testing This sequence change replaces lysine with methionine at codon 1255 of the CDH23 protein (p.Lys1255Met). The lysine residue is highly conserved and there is a moderate physicochemical difference between lysine and methionine. This variant is present in population databases (rs372158876, ExAC 0.1%). This variant has not been reported in the literature in individuals with CDH23-related disease. ClinVar contains an entry for this variant (Variation ID: 426618). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: Not Available; Align-GVGD: "Class C65"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Natera, Inc. RCV001272565 SCV001454657 uncertain significance Usher syndrome type 1 2019-10-28 no assertion criteria provided clinical testing

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