ClinVar Miner

Submissions for variant NM_015450.3(POT1):c.1810G>A (p.Glu604Lys) (rs753762757)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000519301 SCV000617700 uncertain significance not provided 2017-10-13 criteria provided, single submitter clinical testing The E604K variant in the POT1 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The E604K variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The E604K 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. In silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret E604K as a variant of uncertain significance.
Invitae RCV000652225 SCV000774093 uncertain significance Melanoma, cutaneous malignant, susceptibility to, 10 2018-08-20 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 604 of the POT1 protein (p.Glu604Lys). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is present in population databases (rs753762757, ExAC 0.008%). This variant has not been reported in the literature in individuals with POT1-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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.

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