Submissions for variant NM_006005.3(WFS1):c.2390A>T (p.Asp797Val)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV002651817	SCV003525510	uncertain significance	not provided	2023-07-29	criteria provided, single submitter	clinical testing	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. This variant disrupts the p.Asp797 amino acid residue in WFS1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 25250959, 29447883). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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) has been performed at Invitae 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. ClinVar contains an entry for this variant (Variation ID: 2203531). This missense change has been observed in individual(s) with WFS1-related conditions (PMID: 21602428, 26875006, 33841295). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces aspartic acid, which is acidic and polar, with valine, which is neutral and non-polar, at codon 797 of the WFS1 protein (p.Asp797Val).
GeneDx	RCV002651817	SCV005078483	pathogenic	not provided	2024-01-09	criteria provided, single submitter	clinical testing	Identified in a patient with optic atrophy, sensorineural hearing loss, and diabetes in published literature (PMID: 26875006); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 37041640, 33841295, 35469785, 25250959, 29447883, 34387732, 26875006, 21602428)