4-6301846-C-T
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
Consequence
NM_006005.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| WFS1 | NM_006005.3 | c.2051C>T | p.Ala684Val | missense_variant | Exon 8 of 8 | ENST00000226760.5 | NP_005996.2 | |
| WFS1 | NM_001145853.1 | c.2051C>T | p.Ala684Val | missense_variant | Exon 8 of 8 | NP_001139325.1 |
Ensembl
Frequencies
GnomAD3 genomes
GnomAD4 exome AF: 0.00000274 AC: 4AN: 1460574Hom.: 0 Cov.: 98 AF XY: 0.00000275 AC XY: 2AN XY: 726644
GnomAD4 genome
ClinVar
Submissions by phenotype
not provided Pathogenic:11
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WFS1: PS2:Very Strong, PP1:Strong, PM2, PM5, PS4:Moderate, PS3:Supporting -
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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) -
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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. -
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). 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%. Experimental studies have shown that this missense change affects WFS1 function (PMID: 21538838). For these reasons, this variant has been classified as Pathogenic. -
Wolfram-like syndrome Pathogenic:4
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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] -
Wolfram syndrome 1 Pathogenic:2
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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. -
Autosomal dominant nonsyndromic hearing loss 6 Pathogenic:2
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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. -
Inborn genetic diseases Pathogenic:1
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. -
Optic atrophy Pathogenic:1
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WFS1-related disorder Pathogenic:1
PS2, PS3, PS4, PM2, PP1, PP3 -
Wolfram syndrome 1;C5680250:Rare genetic deafness Pathogenic:1
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. -
WFS1-spectrum disorder Pathogenic:1
A known missense variant, c.2051C>T (ClinVar ID: VCV000030556.43; Chan YH et al., 2023) in exon 8 of WFS1 was observed in a heterozygous state in Proband. On segregation, the variant was not observed in her parents. This variant is present in heterozygous state in 4 individuals in the gnomAD (v4.1.0) population database and absent in our in-house data of 3527 exomes. Functional studies using HEK cell line showed decreased expression of WFS1 protein (Rendtorff ND et al., 2011). The clinical findings observed in the proband are in concordance with WFS1-spectrum disorder. Thus, the above-mentioned findings suggest a diagnosis of this disorder in her. -
Autosomal dominant nonsyndromic hearing loss Pathogenic:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at