Submissions for variant NM_006005.3(WFS1):c.1237T>G (p.Phe413Val)

gnomAD frequency: 0.00004  dbSNP: rs71524356

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000152671	SCV000202032	likely benign	not specified	2016-06-23	criteria provided, single submitter	clinical testing	p.Phe413Val in Exon 8 of WFS1: This variant is not expected to have clinical sig nificance due to a lack of conservation across species, including mammals. Many mammals, including other primates, have a valine (Val) at this position despite high nearby amino acid conservation. In addition, computational analyses (PolyPh en2, SIFT, AlignGVGD) do not suggest a high likelihood of impact to the protein. This variant has been identified in 4/66740 of European chromosomes by the Exom e Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs71524356 ).
GeneDx	RCV001719944	SCV000716729	likely benign	not provided	2021-04-06	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001719944	SCV002314483	uncertain significance	not provided	2024-11-28	criteria provided, single submitter	clinical testing	This sequence change replaces phenylalanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 413 of the WFS1 protein (p.Phe413Val). This variant is present in population databases (rs71524356, 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: 166584). 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.
Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic	RCV002509253	SCV002817348	benign	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 rs71524356 in Wolfram's syndrome yet.
Ambry Genetics	RCV002514938	SCV003694629	likely benign	Inborn genetic diseases	2021-09-16	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.
PreventionGenetics, part of Exact Sciences	RCV004737235	SCV005360200	uncertain significance	WFS1-related disorder	2024-06-06	no assertion criteria provided	clinical testing	The WFS1 c.1237T>G variant is predicted to result in the amino acid substitution p.Phe413Val. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0093% of alleles in individuals of European (Non-Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.