ClinVar Miner

Submissions for variant NM_006005.3(WFS1):c.1297G>A (p.Ala433Thr)

gnomAD frequency: 0.00006  dbSNP: rs138771366
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Total submissions: 5
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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 RCV000152674 SCV000202036 uncertain significance not specified 2016-02-07 criteria provided, single submitter clinical testing The p.Ala433Thr variant in WFS1 has not been previously reported in individuals with hearing loss or Wolfram syndrome. This variant has been identified in 8/66 730 European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac. broadinstitute.org; dbSNP rs138771366); however, its frequency is not high enoug h to rule out a pathogenic role. Computational prediction tools and conservation analyses suggest that the p.Ala433Thr variant may not impact the protein, thoug h this information is not predictive enough to rule out pathogenicity. In summar y, the clinical significance of the p.Ala433Thr variant is uncertain.
Labcorp Genetics (formerly Invitae), Labcorp RCV001298335 SCV001487387 uncertain significance not provided 2024-11-05 criteria provided, single submitter clinical testing This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 433 of the WFS1 protein (p.Ala433Thr). This variant is present in population databases (rs138771366, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with WFS1-related conditions. ClinVar contains an entry for this variant (Variation ID: 166587). 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) indicates that this missense variant is not expected to disrupt WFS1 protein function with a negative predictive value of 95%. 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.
Ambry Genetics RCV003278672 SCV003954148 uncertain significance Inborn genetic diseases 2023-04-12 criteria provided, single submitter clinical testing The c.1297G>A (p.A433T) alteration is located in exon 8 (coding exon 7) of the WFS1 gene. This alteration results from a G to A substitution at nucleotide position 1297, causing the alanine (A) at amino acid position 433 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Fulgent Genetics, Fulgent Genetics RCV005025231 SCV005660232 uncertain significance Cataract 41; Wolfram syndrome 1; Autosomal dominant nonsyndromic hearing loss 6; Type 2 diabetes mellitus; Wolfram-like syndrome 2024-01-05 criteria provided, single submitter clinical testing
Division of Human Genetics, Children's Hospital of Philadelphia RCV000477805 SCV000536826 uncertain significance Autosomal dominant nonsyndromic hearing loss 6 2015-10-30 no assertion criteria provided research

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