4-6301846-C-T
Position:
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_006005.3(WFS1):c.2051C>T(p.Ala684Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,460,574 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A684G) has been classified as Likely pathogenic.
Frequency
Genomes: not found (cov: 34)
Exomes 𝑓: 0.0000027 ( 0 hom. )
Consequence
WFS1
NM_006005.3 missense
NM_006005.3 missense
Scores
13
3
3
Clinical Significance
Conservation
PhyloP100: 7.45
Genes affected
WFS1 (HGNC:12762): (wolframin ER transmembrane glycoprotein) This gene encodes a transmembrane protein, which is located primarily in the endoplasmic reticulum and ubiquitously expressed with highest levels in brain, pancreas, heart, and insulinoma beta-cell lines. Mutations in this gene are associated with Wolfram syndrome, also called DIDMOAD (Diabetes Insipidus, Diabetes Mellitus, Optic Atrophy, and Deafness), an autosomal recessive disorder. The disease affects the brain and central nervous system. Mutations in this gene can also cause autosomal dominant deafness 6 (DFNA6), also known as DFNA14 or DFNA38. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Mar 2009]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PM1
In a topological_domain Lumenal (size 216) in uniprot entity WFS1_HUMAN there are 92 pathogenic changes around while only 24 benign (79%) in NM_006005.3
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr4-6301846-C-G is described in Lovd as [Likely_pathogenic].
PP3
MetaRNN computational evidence supports a deleterious effect, 0.947
PP5
Variant 4-6301846-C-T is Pathogenic according to our data. Variant chr4-6301846-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 30556.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-6301846-C-T is described in Lovd as [Likely_pathogenic]. Variant chr4-6301846-C-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| WFS1 | NM_006005.3 | c.2051C>T | p.Ala684Val | missense_variant | 8/8 | ENST00000226760.5 | NP_005996.2 | |
| WFS1 | NM_001145853.1 | c.2051C>T | p.Ala684Val | missense_variant | 8/8 | NP_001139325.1 |
Ensembl
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
34
GnomAD4 exome AF: 0.00000274 AC: 4AN: 1460574Hom.: 0 Cov.: 98 AF XY: 0.00000275 AC XY: 2AN XY: 726644
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4
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1460574
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98
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2
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726644
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GnomAD4 genome
GnomAD4 genome
Cov.:
34
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:24
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:11
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Nov 30, 2021 | Published functional studies of the A684V variant in HEK cells showed reduced protein levels compared to wild-type wolframin, strongly indication that the variant in disease-causing (Rendtorff et al., 2011); In silico analysis supports that this missense variant does not alter protein structure/function; Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 28432734, 29529044, 21067485, 21538838, 11295831, 28468959, 12022290, 26435059, 22238590, 26875006, 30577886, 32567228, 33098801, 33841295, 32645618) - |
| Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Aug 22, 2018 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jan 01, 2024 | WFS1: PS2:Very Strong, PP1:Strong, PM2, PM5, PS4:Moderate, PS3:Supporting - |
| Pathogenic, criteria provided, single submitter | clinical testing | Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia | Feb 05, 2015 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, Amsterdam University Medical Center | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Nov 06, 2023 | This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 684 of the WFS1 protein (p.Ala684Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of autosomal dominant Wolfram syndrome and autosomal recessive Wolfram-like syndrome (PMID: 11295831, 21067485, 21538838, 22238590, 29529044). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 30556). 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 expected to disrupt WFS1 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects WFS1 function (PMID: 21538838). For these reasons, this variant has been classified as Pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Clinical Genetics Laboratory, Skane University Hospital Lund | Mar 19, 2024 | - - |
| Likely pathogenic, no assertion criteria provided | clinical testing | Genetics and Genomic Medicine Centre, NeuroGen Healthcare, NeuroGen Healthcare | Dec 14, 2020 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics | Jul 16, 2019 | The best available variant frequency is uninformative because there are too few occurrences in population data. Found in at least one symptomatic patient. Predicted to have a damaging effect on the protein. The gain of a new splice site is predicted. Occurs in three or more cases with a recessive pathogenic variant in the same gene. Damaging to protein function(s) relevant to disease mechanism. Moderate co-segregation with disease, and data include affected and unaffected individuals from multiple families. - |
| Pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Wolfram-like syndrome Pathogenic:4
| Pathogenic, no assertion criteria provided | literature only | OMIM | Jun 01, 2011 | - - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital | Dec 13, 2024 | The identified heterozygous missense variant in WFS1 gene is predicted to be damaging by various in-silico predictions[PP3], is present in the mutational hotspot region[PM1], is absent from normal population database[PM2]. This is inherited from father symptomatic father. It has been reported 21 times as pathogenic and likely pathogenic in clinvar [Clinvar ID: 30556]. This variant is well reported in literature [PMID: 21538838, 37041640, 36933359] - |
| Pathogenic, criteria provided, single submitter | clinical testing | Center of Genomic medicine, Geneva, University Hospital of Geneva | Sep 13, 2019 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München | Oct 13, 2017 | - - |
Autosomal dominant nonsyndromic hearing loss 6 Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | 3billion | May 22, 2022 | The variant is not observed in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.89; 3Cnet: 0.86). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000030556). The variant has been previously reported as assumed (i.e. paternity and maternity not confirmed) de novo in at least one similarly affected unrelated individual (PMID: 29529044). A different missense change at the same codon (p.Ala684Thr) has been reported to be associated with WFS1 related disorder (PMID: 20875904). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. - |
| Likely pathogenic, no assertion criteria provided | clinical testing | Genomics England Pilot Project, Genomics England | - | - - |
Wolfram syndrome 1 Pathogenic:2
| Pathogenic, no assertion criteria provided | literature only | OMIM | Jun 01, 2011 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | May 22, 2024 | Variant summary: WFS1 c.2051C>T (p.Ala684Val) results in a non-conservative amino acid change located in the Wolframin, cysteine-rich domain (IPR045400) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The frequency data for this variant in gnomAD is considered unreliable, as metrics indicate poor data quality at this position. c.2051C>T has been reported in the literature in multiple individuals affected with optic atrophy and hearing impairment or Wolfram Syndrome 1, including at least one de novo case (Rendtorff_2011, Baker_2019). In addition, this variant was co-segregated with disease in multiple families (Rendtorff_2011). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (Rendtorff_2011). The following publications have been ascertained in the context of this evaluation (PMID: 30577886, 21538838). ClinVar contains an entry for this variant (Variation ID: 30556). Based on the evidence outlined above, the variant was classified as pathogenic. - |
Inborn genetic diseases Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 05, 2024 | The c.2051C>T (p.A684V) alteration is located in exon 8 (coding exon 7) of the WFS1 gene. This alteration results from a C to T substitution at nucleotide position 2051, causing the alanine (A) at amino acid position 684 to be replaced by a valine (V). The WFS1 c.2051C>T alteration was flagged as a low confidence call in the Genome Aggregation Database (gnomAD). This variant has been reported to segregate in members from multiple families with features consistent with autosomal dominant Wolfram-like syndrome (Rendtorff, 2011); this variant has also been determined to be the result of a de novo variant in one individual (Ambry internal data). This variant has been identified in the homozygous state and/or in conjunction with other WFS1 variant(s) in individual(s) with features consistent with autosomal recessive WFS1-related Wolfram syndrome; in at least one instance, the variants were identified in trans (Tessa, 2001; Rendtorff, 2011). Another alteration at the same codon, c.2050G>A (p.A684T), has been described in individuals with autosomal recessive WFS1-related Wolfram syndrome (Waschbisch, 2011; Xavier, 2016). This amino acid position is highly conserved in available vertebrate species. Experimental evidence demonstrated reduced protein expression associated with this variant (Rendtorff, 2011). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. - |
Wolfram syndrome 1;C5680250:Rare genetic deafness Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Mar 26, 2017 | The p.Ala684Val variant in WFS1 has been reported in 6 individuals with autosoma l dominant Wolfram-like syndrome (hearing loss and optic atrophy) and segregated in >10 affected family members across 4 different families (Rendtoff 2011, Maja nder 2016). In one of these families, a sib-pair presented with clinical feature s of autosomal recessive Wolfram syndrome (juvenile-onset diabetes mellitus, opt ic atrophy, bilateral profound sensorineural hearing loss from birth or infancy, and congenital cataracts), and were found to carry the p.Ala684Val in compound heterozygosity with a second WFS1 variant (p.Val415del). The p.Ala684Val variant was inherited from their father, who had Wolfram-like features, and the other v ariant was inherited from their mother who was unaffected (Mets 2010, Rendtoff 2 011). Two additional individuals with autosomal recessive Wolfram syndrome were reported with the p.Ala684Val variant, one of whom also had a second pathogenic variant in WFS1 (Tessa 2001, Aloi 2012). In addition, in vitro expression studie s suggest that the p.Ala684Val variant may impact normal expression of WFS1 (Ren dtorff 2011). Furthermore, this variant is reported in the ClinVar database as a pathogenic variant (Variation ID# 30556), and was absent in large population st udies. In summary, this variant meets criteria to be classified as pathogenic fo r both autosomal recessive Wolfram syndrome and autosomal dominant Wolfram-like syndrome based upon reported familial cases, absence from controls, and function al evidence. - |
Optic atrophy Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg | Jan 01, 2023 | - - |
WFS1-related disorder Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center | Apr 29, 2022 | PS2, PS3, PS4, PM2, PP1, PP3 - |
Autosomal dominant nonsyndromic hearing loss Pathogenic:1
| Pathogenic, criteria provided, single submitter | research | Center for Statistical Genetics, Columbia University | Nov 08, 2024 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Benign
T;T
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
.;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D
MetaSVM
Pathogenic
D
MutationAssessor
Uncertain
M;M
PrimateAI
Uncertain
T
PROVEAN
Benign
N;N
REVEL
Pathogenic
Sift
Pathogenic
D;D
Sift4G
Pathogenic
D;D
Polyphen
D;D
Vest4
MutPred
Loss of helix (P = 0.0104);Loss of helix (P = 0.0104);
MVP
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at