4-6301848-C-T
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PM5PP3PP5
The NM_006005.3(WFS1):c.2053C>T(p.Arg685Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000179 in 1,612,938 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R685P) has been classified as Pathogenic.
Frequency
Consequence
NM_006005.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
WFS1 | NM_006005.3 | c.2053C>T | p.Arg685Cys | missense_variant | Exon 8 of 8 | ENST00000226760.5 | NP_005996.2 | |
WFS1 | NM_001145853.1 | c.2053C>T | p.Arg685Cys | missense_variant | Exon 8 of 8 | NP_001139325.1 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000204 AC: 31AN: 152156Hom.: 0 Cov.: 34
GnomAD3 exomes AF: 0.000212 AC: 53AN: 250204Hom.: 0 AF XY: 0.000229 AC XY: 31AN XY: 135344
GnomAD4 exome AF: 0.000175 AC: 256AN: 1460664Hom.: 0 Cov.: 98 AF XY: 0.000173 AC XY: 126AN XY: 726668
GnomAD4 genome AF: 0.000210 AC: 32AN: 152274Hom.: 0 Cov.: 34 AF XY: 0.000228 AC XY: 17AN XY: 74454
ClinVar
Submissions by phenotype
Type 2 diabetes mellitus;C1833021:Autosomal dominant nonsyndromic hearing loss 6;C3280358:Wolfram-like syndrome;C3805412:Cataract 41;C4551693:Wolfram syndrome 1 Pathogenic:1Uncertain:1
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not provided Uncertain:2
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 685 of the WFS1 protein (p.Arg685Cys). This variant is present in population databases (rs112967046, gnomAD 0.06%). This missense change has been observed in individual(s) with clinical features of autosomal recessive WFS1-related conditions (PMID: 34789499). ClinVar contains an entry for this variant (Variation ID: 393391). 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 expected to disrupt WFS1 protein function with a positive 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. -
Reported with a second variant (phase unknown) in a patient suspected to have monogenic diabetes in published literature (PMID: 34789499); however, clinical information not provided; 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: 11920861, 34789499, 37277527) -
Wolfram syndrome 1 Pathogenic:1
Homozygosity of a very rare variant predicted deleterious by most prediction programs and classified as likely pathogenic by one CLinVar entry. -
Optic atrophy Uncertain:1
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WFS1-related disorder Uncertain:1
The WFS1 c.2053C>T variant is predicted to result in the amino acid substitution p.Arg685Cys. This variant has been reported in the compound heterozygous state along with a truncating variant in a patient with features consistent with Wolfram syndrome (Table S4 and S8, Colclough et al. 2022. PubMed ID: 34789499). This variant was also reported in a study of the relationship between Wolfram syndrome carrier status and suicide (Crawford et al. 2002. PubMed ID: 11920861). A different substitutions at the same codon have been reported in patients with sensorineural hearing loss or early-onset diabetes (p.Arg685Pro, Bramhall et al. 2008. PubMed ID: 18518985; p.Arg685His, Artuso et al. 2015. PubMed ID: 25048417). This variant is reported in 0.056% of alleles in individuals of South Asian descent in gnomAD. While we suspect this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -
Monogenic diabetes Uncertain:1
ACMG Criteria: PP3 -
Autosomal dominant nonsyndromic hearing loss 6 Uncertain:1
The variant is observed at an allele frequency greater than expected for the associated disorder in the gnomAD v4.0.0 dataset. In silico tool predictions suggest damaging effect of the variant on gene or gene product [REVEL: 0.80 (>=0.6, sensitivity 0.68 and specificity 0.92); 3Cnet: 0.93 (>=0.6, sensitivity 0.72 and precision 0.9)]. Different missense changes at the same codon (p.Arg685His, p.Arg685Pro) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000045446, VCV000215395 / PMID: 18518985). Therefore, this variant is classified as uncertain significance according to the recommendation of ACMG/AMP guideline. -
Meniere disease Uncertain:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at