ClinVar Miner

Submissions for variant NM_006005.3(WFS1):c.1037C>T (p.Pro346Leu)

gnomAD frequency: 0.00001  dbSNP: rs773900146
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine,Mass General Brigham Personalized Medicine RCV000221182 SCV000272908 uncertain significance not specified 2015-02-06 criteria provided, single submitter clinical testing The p.Pro346Leu variant in WFS1 has been reported as compound heterozygous in 1 Caucasian individual with Wolfram syndrome (Cano 2007). This variant has also be en identified in 1/6748 European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org); however, its frequency is not high enou gh to rule out a pathogenicity. Computational prediction tools and conservation analyses suggest that the p.Pro346Leu variant may impact the protein, though thi s information is not predictive enough to determine pathogenicity. In summary, t he clinical significance of the p.Pro346Leu variant is uncertain.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen RCV001291575 SCV001480111 likely pathogenic not provided 2021-02-01 criteria provided, single submitter clinical testing
Invitae RCV001291575 SCV002250388 uncertain significance not provided 2021-09-24 criteria provided, single submitter clinical testing This sequence change replaces proline with leucine at codon 346 of the WFS1 protein (p.Pro346Leu). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and leucine. This variant is present in population databases (rs773900146, ExAC 0.02%). This missense change has been observed in individual(s) with autosomal recessive Wolfram syndrome (PMID: 17568405). ClinVar contains an entry for this variant (Variation ID: 229634). 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: "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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