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: 6
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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
Labcorp Genetics (formerly Invitae), Labcorp RCV001291575 SCV002250388 pathogenic not provided 2024-10-26 criteria provided, single submitter clinical testing This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 346 of the WFS1 protein (p.Pro346Leu). This variant is present in population databases (rs773900146, gnomAD 0.01%). This missense change has been observed in individual(s) with autosomal recessive Wolfram syndrome (PMID: 17568405; internal data). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 229634). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on WFS1 protein function. For these reasons, this variant has been classified as Pathogenic.
MGZ Medical Genetics Center RCV002288843 SCV002580002 likely pathogenic Wolfram syndrome 1 2022-05-25 criteria provided, single submitter clinical testing
CeGaT Center for Human Genetics Tuebingen RCV001291575 SCV004034044 uncertain significance not provided 2023-07-01 criteria provided, single submitter clinical testing WFS1: PM2, PM3:Supporting
Fulgent Genetics, Fulgent Genetics RCV005025353 SCV005660212 uncertain significance Cataract 41; Wolfram syndrome 1; Autosomal dominant nonsyndromic hearing loss 6; Type 2 diabetes mellitus; Wolfram-like syndrome 2024-03-05 criteria provided, single submitter clinical testing

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