Submissions for variant NM_006005.3(WFS1):c.792C>G (p.Phe264Leu)

gnomAD frequency: 0.00007  dbSNP: rs373669861

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000612750	SCV000711246	likely benign	not specified	2016-07-21	criteria provided, single submitter	clinical testing	p.Phe264Leu in exon 7 of WFS1: This variant is not expected to have clinical sig nificance due to a lack of conservation across species, including mammals. Of no te, 9 different species including 3 mammals (Crab-eating macaque, david's myotis (bat), and oppossum) have a Leucine (Leu) at this position despite high nearby amino acid conservation. In addition, computational prediction tools do not sugg est a high likelihood of impact to the protein It has been identified in 2/10328 African chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broa dinstitute.org; dbSNP rs373669861).
Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic	RCV002509080	SCV002774904	likely 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 rs373669861 in Wolfram's syndrome yet.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002532737	SCV003285788	uncertain significance	not provided	2023-12-01	criteria provided, single submitter	clinical testing	This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 264 of the WFS1 protein (p.Phe264Leu). This variant is present in population databases (rs373669861, 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: 504707). 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.
PreventionGenetics, part of Exact Sciences	RCV004530733	SCV004117283	uncertain significance	WFS1-related disorder	2023-04-24	criteria provided, single submitter	clinical testing	The WFS1 c.792C>G variant is predicted to result in the amino acid substitution p.Phe264Leu. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.020% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/4-6296847-C-G). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Mayo Clinic Laboratories, Mayo Clinic	RCV002532737	SCV005410512	uncertain significance	not provided	2024-07-24	criteria provided, single submitter	clinical testing	BP4, PM2
Fulgent Genetics, Fulgent Genetics	RCV005034186	SCV005664703	uncertain significance	Cataract 41; Wolfram syndrome 1; Autosomal dominant nonsyndromic hearing loss 6; Type 2 diabetes mellitus; Wolfram-like syndrome	2024-01-24	criteria provided, single submitter	clinical testing