ClinVar

Description

The c.1672C>T (p.Arg558Cys) missense variant identified in WFS1 has been reported in homozygous as well as in compound heterozygous states in individuals affected with autosomal recessive Wolfram syndrome [PMID: 30957632, 17568405, 21446023], reported as heterozygous in individuals affected with autosomal dominant Wolfram-like syndrome [PMID: 27395765], in three individuals in a cohort of 1019 patients with type 1 diabetes [PMID:31264968] and in a single patient in a large cohort of type 2 diabetes patients [PMID:33046911]. It was also reported as a variant of uncertain significance in an individual affected with ataxia and polyneuropathy and in an individual affected with familial schizophrenia [PMID: 25133958, 11244483]. The variant has 0.0003284 allele frequency in the gnomAD(v3) database (50 out of 152262 heterozygous alleles, no homozygotes), 0.0006277 allele frequency in the gnomAD(v2) database (177 out of 281960 heterozygous alleles,1 homozygote) and 0.01341 allele frequency in the Ashkenazi Jewish subpopulation represented in gnomAD(v2) database (139 out of 10366 heterozygous alleles, 1 homozygous allele). Multiple independent laboratories have reported this variant in the ClinVar database with conflicting interpretations of pathogenicity for WFS1-related disorders [Variation ID: 198835; Pathogenic = 2, Likely pathogenic = 2, and Uncertain significance = 3]. This variant replaces highly conserved arginine residue [Arg558] and is predicted deleterious by multiple in silico tools (CADD score = 32, REVEL score = 0.816). Based on the available evidence,the heterozygous c.1672C>T (p.Arg558Cys) missense variant identified in the WFS1 gene is reported as a Variant of Uncertain Significance