Submissions for variant NM_006005.3(WFS1):c.1706C>T (p.Ala569Val)

gnomAD frequency: 0.00042  dbSNP: rs144492050

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000615776	SCV000711251	uncertain significance	not specified	2017-07-06	criteria provided, single submitter	clinical testing	The p.Ala569Val variant in WFS1 has been reported in the heterozygous state in 1 French individual with clinical features of Wolfram syndrome (Chaussenot 2015), but has also been identified in 0.15% (37/24030) of African chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs1 44492050). Although this variant has been seen in the general population, its fr equency is not high enough to rule out a pathogenic role. Computational predicti on tools and conservation analysis do not provide strong support for or against an impact to the protein. In summary, the clinical significance of the p.Ala569V al variant is uncertain.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001366053	SCV001562342	uncertain significance	not provided	2024-11-30	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 569 of the WFS1 protein (p.Ala569Val). This variant is present in population databases (rs144492050, gnomAD 0.2%). This missense change has been observed in individual(s) with clinical features of Wolfram syndrome (PMID: 24890733). ClinVar contains an entry for this variant (Variation ID: 504710). 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 80%. 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	RCV001366053	SCV001826058	likely benign	not provided	2020-08-18	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 24890733)
Ambry Genetics	RCV002532738	SCV003701977	likely benign	Inborn genetic diseases	2021-08-27	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic	RCV003126842	SCV003801427	uncertain risk allele	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 rs144492050 in Wolfram's syndrome yet.
Fulgent Genetics, Fulgent Genetics	RCV005034188	SCV005672326	likely benign	Cataract 41; Wolfram syndrome 1; Autosomal dominant nonsyndromic hearing loss 6; Type 2 diabetes mellitus; Wolfram-like syndrome	2024-02-21	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004737882	SCV005366666	uncertain significance	WFS1-related disorder	2024-06-10	no assertion criteria provided	clinical testing	The WFS1 c.1706C>T variant is predicted to result in the amino acid substitution p.Ala569Val. This variant was reported in an individual with features consistent with Wolfram syndrome, although a second potentially causative variant was not identified (Chaussenot et al. 2015. PubMed ID: 24890733). This variant is reported in 0.17% of alleles in individuals of African descent in gnomAD. Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.