4-6301615-C-T
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM2PM5PP3_StrongPP5
The NM_006005.3(WFS1):c.1820C>T(p.Pro607Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000211 in 1,614,118 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. P607R) has been classified as Likely pathogenic.
Frequency
Consequence
NM_006005.3 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Likely_pathogenic. Variant got 9 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
WFS1 | NM_006005.3 | c.1820C>T | p.Pro607Leu | missense_variant | Exon 8 of 8 | ENST00000226760.5 | NP_005996.2 | |
WFS1 | NM_001145853.1 | c.1820C>T | p.Pro607Leu | missense_variant | Exon 8 of 8 | NP_001139325.1 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000723 AC: 11AN: 152200Hom.: 0 Cov.: 34
GnomAD3 exomes AF: 0.0000636 AC: 16AN: 251406Hom.: 0 AF XY: 0.0000662 AC XY: 9AN XY: 135882
GnomAD4 exome AF: 0.0000157 AC: 23AN: 1461800Hom.: 0 Cov.: 99 AF XY: 0.0000110 AC XY: 8AN XY: 727210
GnomAD4 genome AF: 0.0000722 AC: 11AN: 152318Hom.: 0 Cov.: 34 AF XY: 0.0000806 AC XY: 6AN XY: 74476
ClinVar
Submissions by phenotype
not provided Pathogenic:1Uncertain:1
Identified in patients with hearing loss or congenital cataracts in published literature; patients were also heterozygous for WFS1 p.(R868H); it is unknown if the two variants are on the same allele (in cis) or on opposite alleles (in trans) (PMID: 36729443, 26969326, 36597107); 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: 26435059, 36729443, 36597107, 26969326, 37719678, 12707373) -
This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 607 of the WFS1 protein (p.Pro607Leu). This variant is present in population databases (rs373862003, gnomAD 0.07%). This missense change has been observed in individual(s) with clinical features of non-syndromic hearing loss (PMID: 26969326). ClinVar contains an entry for this variant (Variation ID: 45441). 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 80%. This variant disrupts the p.Pro607 amino acid residue in WFS1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12707373). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. -
not specified Uncertain:2
Variant summary: WFS1 c.1820C>T (p.Pro607Leu) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 6.4e-05 in 251406 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in WFS1 causing Wolfram Syndrome 1, allowing no conclusion about variant significance. c.1820C>T has been reported in the literature in several individuals undergoing multigene panel testing for hearing loss or inherited eye diseases (congenital cataracts), where it is frequently reported together with c.2603G>A (p.Arg868His), although phase has not been specified (e.g. Sloan-Heggen_2016, Li_2023, Ma_2023). These reports do not provide unequivocal conclusions about association of the variant with Wolfram Syndrome 1. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 36729443, 36597107, 26969326). ClinVar contains an entry for this variant (Variation ID: 45441). Based on the evidence outlined above, the variant was classified as uncertain significance. -
The Pro607Leu variant in WFS1 has not been reported in affected individuals, but has been identified in 1/8600 European American chromosomes from a broad popula tion by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/). Although this variant has been seen in the general population, its frequency is not high enough to rule out a pathogenic role. Computational analyses (biochemic al amino acid properties, conservation, AlignGVGD, PolyPhen2, and SIFT) do not p rovide strong support for or against an impact to the protein. In summary, addit ional information is needed to fully assess the clinical significance of the Pro 607Leu variant. -
Type 2 diabetes mellitus;C1833021:Autosomal dominant nonsyndromic hearing loss 6;C3280358:Wolfram-like syndrome;C3805412:Cataract 41;C4551693:Wolfram syndrome 1 Pathogenic:1
- -
Inborn genetic diseases Uncertain:1
Identified in the heterozygous state with a second WFS1 variant in a patient with sporadic non-syndromic hearing loss (Sloan-Heggen, 2016)._x000D_ _x000D_ Unlikely to be causative of autosomal dominant WFS1-related Wolfram syndrome. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
Monogenic diabetes Uncertain:1
ACMG criteria: PP3 (0.846 + 9 predictors), PM2_supporting (based on ClinGen HL approved rules 9/28/18, says can use PM2 as supporting if MAF is <0.007% and MAF of c.1820C>T in gnomAD is 0.0069%)= VUS Note: in PMID 26969326, variant ID'd in patient with sporadic NSHL, in trans with other WFS1 variant (c.2603G>A p.R868H; has REVEL score of 0.877/PP3, can use PM2-supporting, also VUS) -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at