ClinVar Miner

Submissions for variant NM_000553.4(WRN):c.2543A>G (p.Tyr848Cys) (rs748334111)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000463979 SCV000541464 uncertain significance Werner syndrome 2018-12-03 criteria provided, single submitter clinical testing This sequence change replaces tyrosine with cysteine at codon 848 of the WRN protein (p.Tyr848Cys). The tyrosine residue is highly conserved and there is a large physicochemical difference between tyrosine and cysteine. While this variant is present in population databases (rs748334111), the frequency information is unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has not been reported in the literature in an individual with a WRN-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies. In summary, this variant is a rare missense change with uncertain impact on protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.

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