Submissions for variant NM_006005.3(WFS1):c.1836G>A (p.Trp612Ter)

gnomAD frequency: 0.00006  dbSNP: rs775158434

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000778740	SCV000915098	uncertain significance	WFS1-Related Spectrum Disorders	2018-11-15	criteria provided, single submitter	clinical testing	The WFS1 c.1836G>A (p.Trp612Ter) variant is a stop-gained variant that is predicted to result in a premature termination of the protein. A literature search was performed for the gene, cDNA change, and amino acid change. No publications were found based on this search. The p.Trp612Ter variant is reported at a frequency of 0.000133 in the European (non-Finnish) population of the Genome Aggregation Database though this is based on two allele in a region of good sequence coverage so the variant is presumed to be rare. Based on the variant frequency, disease prevalence, disease penetrance, and inheritance mode, this variant could not be ruled out of causing disease. Due to the potential impact of stop-gained variants and the lack of clarifying evidence, this variant is classified as a variant of unknown significance but suspicious for pathogenicity 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	RCV003546599	SCV004273433	pathogenic	not provided	2024-01-03	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Trp612*) in the WFS1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 279 amino acid(s) of the WFS1 protein. This variant is present in population databases (no rsID available, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with WFS1-related conditions. ClinVar contains an entry for this variant (Variation ID: 631948). This variant disrupts a region of the WFS1 protein in which other variant(s) (p.Pro885Leu) have been determined to be pathogenic (PMID: 10521293, 16806192, 28432734). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.