ClinVar Miner

Submissions for variant NM_000553.5(WRN):c.3209_3211delGTCinsTTT (p.Cys1070_Pro1071delinsPheSer) (rs878854138)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000234297 SCV000285553 uncertain significance Werner syndrome 2017-08-11 criteria provided, single submitter clinical testing This variant, c.3209_3211delinsTTT, is a complex sequence change that replaces two amino acids, cysteine and proline with phenyalanine and serine at codons 1070-1071 of the WRN protein (p.Cys1070_Pro1071delinsPheSer). The cysteine and proline residues are moderately conserved. This variant is reported as two separate single-nucleotide changes in population databases (c.3209G>T, ExAC 0.1% and c.3211C>T, ExAC 0.1%). However, in the read data for all individuals displayed in the ExAC browser, these two variants are in cis. This recapitulates the variant observed here (c.3209_3211delinsTTT) and indicates that this variant is very likely present in the population databases at 0.1%. This variant has not been reported in the literature in individuals with WRN-related disease. ClinVar contains an entry for this variant (Variation ID: 238148). While algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that the two missense changes, p.Cys1070Phe and p.Pro1071Ser are likely to be tolerated independently, it is uncertain how these two amino acid changes in combination affect protein function. 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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