Submissions for variant NM_006005.3(WFS1):c.1184T>A (p.Val395Asp)

gnomAD frequency: 0.00003  dbSNP: rs769744865

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000825500	SCV000966804	uncertain significance	not specified	2018-05-22	criteria provided, single submitter	clinical testing	The p.Val395Asp variant in WFS1 has not been previously reported in individuals with hearing loss or Wolfram syndrome. This variant has been reported in 0.005% (6/126670) of European chromosomes by the Genome Aggregation Database (gnomAD, h ttp://gnomad.broadinstitute.org; dbSNP rs769744865). Computational prediction to ols and conservation analyses suggest that this variant may not impact the prote in, though this information is not predictive enough to rule out pathogenicity. In summary, the clinical significance of the p.Val395Asp variant is uncertain. ACMG/AMP Criteria applied: BP4.
Invitae	RCV001858397	SCV002152214	uncertain significance	not provided	2024-01-14	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 395 of the WFS1 protein (p.Val395Asp). This variant is present in population databases (rs769744865, gnomAD 0.005%). 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: 666955). 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.
Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic	RCV002509559	SCV002817358	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 rs769744865 in Wolfram's syndrome yet.