Submissions for variant NM_006005.3(WFS1):c.2051C>T (p.Ala684Val)

dbSNP: rs387906930

Total submissions: 18

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000200668	SCV000252536	pathogenic	not provided	2021-11-30	criteria provided, single submitter	clinical testing	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)
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000200668	SCV000258031	pathogenic	not provided	2015-02-05	criteria provided, single submitter	clinical testing
Institute Of Human Genetics Munich, Klinikum Rechts Der Isar, Tu München	RCV000023514	SCV000680436	pathogenic	Wolfram-like syndrome	2017-10-13	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000605882	SCV000731501	pathogenic	Wolfram syndrome 1; Rare genetic deafness	2017-03-26	criteria provided, single submitter	clinical testing	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.
Ambry Genetics	RCV000623116	SCV000742873	pathogenic	Inborn genetic diseases	2017-08-24	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000200668	SCV000862912	pathogenic	not provided	2018-08-22	criteria provided, single submitter	clinical testing
Athena Diagnostics Inc	RCV000200668	SCV001146651	pathogenic	not provided	2019-07-16	criteria provided, single submitter	clinical testing	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.
Invitae	RCV000200668	SCV001589181	pathogenic	not provided	2023-11-06	criteria provided, single submitter	clinical testing	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.
Center of Genomic medicine, Geneva, University Hospital of Geneva	RCV000023514	SCV001739301	pathogenic	Wolfram-like syndrome	2019-09-13	criteria provided, single submitter	clinical testing
3billion	RCV001542531	SCV002521051	pathogenic	Autosomal dominant nonsyndromic hearing loss 6	2022-05-22	criteria provided, single submitter	clinical testing	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.
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV002280094	SCV002568322	pathogenic	WFS1-related disorder	2022-04-29	criteria provided, single submitter	clinical testing	PS2, PS3, PS4, PM2, PP1, PP3
CeGaT Center for Human Genetics Tuebingen	RCV000200668	SCV004702639	pathogenic	not provided	2024-01-01	criteria provided, single submitter	clinical testing	WFS1: PS2:Very Strong, PP1:Strong, PM2, PM5, PS4:Moderate, PS3:Supporting
OMIM	RCV000023514	SCV000044805	pathogenic	Wolfram-like syndrome	2011-06-01	no assertion criteria provided	literature only
OMIM	RCV000023515	SCV000044806	pathogenic	Wolfram syndrome 1	2011-06-01	no assertion criteria provided	literature only
Genomics England Pilot Project, Genomics England	RCV001542531	SCV001760141	likely pathogenic	Autosomal dominant nonsyndromic hearing loss 6		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000200668	SCV001807389	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000200668	SCV001917382	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000200668	SCV001951728	pathogenic	not provided		no assertion criteria provided	clinical testing