Submissions for variant NM_006005.3(WFS1):c.1219C>T (p.His407Tyr)

gnomAD frequency: 0.00004  dbSNP: rs151244358

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000152670	SCV000202031	uncertain significance	not specified	2013-10-11	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Benign. The His407Tyr varia nt in WFS1 has not been reported in individuals with hearing loss, but has been identified in 0.04% (2/4406) of African American chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/; dbSNP rs151244358). Compu tational analyses (biochemical amino acid properties, conservation, AlignGVGD, P olyPhen2, and SIFT) suggest that the His407Tyr variant may not impact the protei n, though this information is not predictive enough to rule out pathogenicity. I n summary, the clinical significance of this variant cannot be determined with c ertainty; however based upon the computational data, we would lean towards a mor e likely benign role.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001308356	SCV001497803	uncertain significance	not provided	2025-01-15	criteria provided, single submitter	clinical testing	This sequence change replaces histidine, which is basic and polar, with tyrosine, which is neutral and polar, at codon 407 of the WFS1 protein (p.His407Tyr). This variant is present in population databases (rs151244358, gnomAD 0.02%). This missense change has been observed in individual(s) with early-onset diabetes (PMID: 37277527). ClinVar contains an entry for this variant (Variation ID: 166583). 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.
Fulgent Genetics, Fulgent Genetics	RCV002505159	SCV002816264	uncertain significance	Cataract 41; Wolfram syndrome 1; Autosomal dominant nonsyndromic hearing loss 6; Type 2 diabetes mellitus; Wolfram-like syndrome	2024-05-08	criteria provided, single submitter	clinical testing
Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic	RCV002509252	SCV002817352	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 rs151244358 in Wolfram's syndrome yet.