ClinVar Miner

Submissions for variant NM_000553.6(WRN):c.1988C>T (p.Thr663Met)

gnomAD frequency: 0.00001  dbSNP: rs752650803
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000800536 SCV000940258 uncertain significance Werner syndrome 2025-01-14 criteria provided, single submitter clinical testing This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 663 of the WRN protein (p.Thr663Met). This variant is present in population databases (rs752650803, gnomAD 0.007%). This variant has not been reported in the literature in individuals affected with WRN-related conditions. ClinVar contains an entry for this variant (Variation ID: 646283). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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.
Breakthrough Genomics, Breakthrough Genomics RCV004693289 SCV005195869 uncertain significance not provided criteria provided, single submitter not provided
Genetic Services Laboratory, University of Chicago RCV003151150 SCV003839228 uncertain significance not specified 2022-05-20 no assertion criteria provided clinical testing DNA sequence analysis of the WRN gene demonstrated a sequence change, c.1988C>T, in exon 18 that results in an amino acid change, p.Thr663Met. This sequence change has been described in the gnomAD database in three heterozygous individuals corresponding to a population frequency of 0.00119% (dbSNP rs752650803). The p.Thr663Met change affects a moderately conserved amino acid residue located in a domain of the WRN protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Thr663Met substitution. This sequence change does not appear to have been previously described in individuals with WRN-related disorders. Due to insufficient evidences and the lack of functional studies, the clinical significance of the p.Thr663Met change remains unknown at this time.

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