ClinVar Genomic variation as it relates to human health

The WFS1 c.1673G>A variant is predicted to result in the amino acid substitution p.Arg558His. This variant in the compound heterozygous or homozygous state has been reported in patients with Wolfram syndrome (Colosimo et al. 2003. PubMed ID: 12754709; Smith et al. 2004. PubMed ID: 15277431; Cano et al. 2007. PubMed ID: 17568405; Chaussenot et al. 2015. PubMed ID: 24890733; Pan et al. 2019. PubMed ID: 31567480). This variant is reported in 0.010% of alleles in individuals of East Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/4-6303195-G-A). This variant is interpreted as likely pathogenic.

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 17568405, 31567480, 27395765, 34426522, 24890733, 33046911, 15277431, 12955714, 12754709, 33841295, 36208030, 35010780, 36227502, 37508961, 36098976, 35469785)

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 558 of the WFS1 protein (p.Arg558His). This variant is present in population databases (rs774265764, gnomAD 0.01%). This missense change has been observed in individual(s) with autosomal recessive Wolfram syndrome (PMID: 12754709, 15277431, 31567480). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 427051). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on WFS1 protein function. For these reasons, this variant has been classified as Pathogenic.

The p.Arg558His variant in WFS1 has been reported in the compound heterozygous or homozygous state in 5 individuals with Wolfram syndrome and 2 individuals with optic atrophy (Colosimo 2003 PMID: 12754709, Smith 2004 PMID: 15277431, Cano 2007 PMID: 17568405, Grenier 2016 PMID: 27395765, Pan 2019 PMID: 31567480, Bonnefond 2020 PMID: 33046911, Charif 2021 PMID: 33841295, Majander 2022 PMID: 35469785). It has also been identified in 0.01% (2/19954) of East Asian chromosomes and 0.01% (10/129060) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant has also been reported in ClinVar (Variation ID 427051). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. Another variant involving this codon (p.Arg558Cys) has been identified in individuals with Wolfram syndrome and is classified as likely pathogenic by this laboratory. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal recessive Wolfram syndrome. ACMG/AMP Criteria applied: PM3_Strong, PM5_Supporting, PM2_Supporting, PP3.

The c.1673G>A (p.R558H) alteration is located in exon 8 (coding exon 7) of the WFS1 gene. This alteration results from a G to A substitution at nucleotide position 1673, causing the arginine (R) at amino acid position 558 to be replaced by a histidine (H). for autosomal recessive WFS1-related Wolfram syndrome; however, it is unlikely to be causative of autosomal dominant Wolfram-like syndrome. Based on data from gnomAD, the A allele has an overall frequency of 0.006% (18/282002) total alleles studied. The highest observed frequency was 0.028% (2/7212) of Other alleles. This variant has been identified in the homozygous state and in conjunction with other WFS1 variants in individuals with features consistent with WFS1-related Wolfram syndrome; in at least one instance, the variants were identified in trans (Jauregui, 2023; Areblom, 2023; Majander, 2022; Charif, 2021; Grenier, 2016; Chaussenot, 2015; Cano, 2007; Smith, 2004; Colosimo, 2003). This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.

The p.(Arg558His) variant is a known pathogenic ressesive variant according to ClinVar and Deafness Variation Database. This variant has been detected together with the p.(Arg517Cys) variant in an individual with moderate-to-profound HL.