ClinVar Miner

Submissions for variant NM_006005.3(WFS1):c.1393G>A (p.Ala465Thr)

gnomAD frequency: 0.00004  dbSNP: rs71524357
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001300363 SCV001489500 uncertain significance not provided 2024-01-31 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 465 of the WFS1 protein (p.Ala465Thr). This variant is present in population databases (rs71524357, gnomAD 0.02%). 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: 1003765). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae 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.
GeneDx RCV001300363 SCV002757707 uncertain significance not provided 2022-05-25 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Fulgent Genetics, Fulgent Genetics RCV002499558 SCV002796979 uncertain significance Cataract 41; Wolfram syndrome 1; Autosomal dominant nonsyndromic hearing loss 6; Type 2 diabetes mellitus; Wolfram-like syndrome 2022-02-09 criteria provided, single submitter clinical testing
Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic RCV003127769 SCV003801361 uncertain significance Wolfram syndrome 1 criteria provided, single submitter research Potent mutations in WFS1 gene are associated with Wolfram's syndrome, an autosomal recessive condition, which cause diabetes mellitus, diabetes insipidus, deafness and optic atrophy. However no sufficient evidence is found to ascertain the role of this particular variant rs71524357 in Wolfram's syndrome yet.
Ambry Genetics RCV004036162 SCV004979911 uncertain significance Inborn genetic diseases 2021-01-08 criteria provided, single submitter clinical testing The c.1393G>A (p.A465T) 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 1393, causing the alanine (A) at amino acid position 465 to be replaced by a threonine (T). The in silico prediction for the p.A465T alteration is inconclusive. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

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