Submissions for variant NM_006005.3(WFS1):c.1839G>A (p.Trp613Ter)

gnomAD frequency: 0.00003  dbSNP: rs143064649

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000285512	SCV000450646	pathogenic	WFS1-Related Spectrum Disorders	2016-09-20	criteria provided, single submitter	clinical testing	The WFS1 c.1839G>A (p.Trp613Ter) stop-gained variant has been reported in four studies in which it is found in a compound heterozygous state with a second variant in four individuals with Wolfram syndrome (Cryns et al. 2003; Marshall et al. 2013; Chaussenot et al. 2015; Bischoff et al. 2015). Of note, five additional affected individuals were compound heterozygous for a different nucleotide change, c.1838G>A, that results in the same stop-gained variant at codon 613 (p.Trp613Ter). The p.Trp613Ter variant was absent from a total of 100 controls and is reported at a frequency of 0.00012 in the European American population of the Exome Sequencing Project, but this is based on only one allele in a region of good sequence coverage so it is presumed to be rare. Based on the potential impact of stop-gained variants and the evidence from the literature, the p.Trp613Ter variant is classified as pathogenic for WFS1-related spectrum disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001861234	SCV002238236	pathogenic	not provided	2022-10-17	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 349320). This premature translational stop signal has been observed in individuals with Wolfram syndrome (PMID: 12955714, 23981289, 28559085). This variant is present in population databases (rs143064649, gnomAD 0.003%). This sequence change creates a premature translational stop signal (p.Trp613*) in the WFS1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 278 amino acid(s) of the WFS1 protein.
GeneDx	RCV001861234	SCV002569686	pathogenic	not provided	2022-03-02	criteria provided, single submitter	clinical testing	Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 278 amino acids are lost, and other loss-of-function variants have been reported downstream in HGMD; This variant is associated with the following publications: (PMID: 33538814, 28559085, 12955714, 26025012, 24890733, 23981289)
Fulgent Genetics, Fulgent Genetics	RCV002502346	SCV002810402	pathogenic	Cataract 41; Wolfram syndrome 1; Autosomal dominant nonsyndromic hearing loss 6; Type 2 diabetes mellitus; Wolfram-like syndrome	2022-01-31	criteria provided, single submitter	clinical testing
Constantin Polychronakos Laboratory, The Research Institute of the McGill University Health Centre	RCV001175324	SCV001250643	pathogenic	Diabetes mellitus		no assertion criteria provided	research	PVS1 PS1 PM1 PM2 PP3 PP4