Submissions for variant NM_006005.3(WFS1):c.409_424dup (p.Val142fs)

dbSNP: rs1362648752

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory, University of Chicago	RCV000499974	SCV000597979	pathogenic	Wolfram syndrome	2017-03-10	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000778736	SCV000915094	pathogenic	WFS1-Related Spectrum Disorders	2019-01-11	criteria provided, single submitter	clinical testing	Across a selection of available literature, the WFS1 c.409_424dupGGCCGTCGCGAGGCTG (p.Val142GlyfsTer110) variant has been identified in in seven individuals with Wolfram syndrome, including in a homozygous state in four individuals from three families and in a compound heterozygous state in three unrelated individuals (Domenech et al. 2004; Chaussenot et al. 2011; Rohayem et al. 2011). A systematic review of disease-causing variants associated with Wolfram syndrome indicated that the p.Val142GlyfsTer110 variant is present in 6.53% of patients and is a common cause of Wolfram syndrome in the Spanish population (de Heredia et al. 2013; Domenech et al. 2004). The variant was absent from 98 control chromosomes and is reported at a frequency of 0.000103 in the Latino population of the Genome Aggregation Database. Based on the collective evidence, the p.Val142GlyfsTer110 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.
Invitae	RCV001385126	SCV001584880	pathogenic	not provided	2022-10-13	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Val142Glyfs*110) in the WFS1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in WFS1 are known to be pathogenic (PMID: 12955714). This variant is present in population databases (rs767046229, gnomAD 0.01%). This premature translational stop signal has been observed in individuals with autosomal recessive Wolfram syndrome (PMID: 1161832, 26875006, 32141364). This variant is also known as 425ins16. ClinVar contains an entry for this variant (Variation ID: 4519). For these reasons, this variant has been classified as Pathogenic.
Genomics England Pilot Project, Genomics England	RCV001542530	SCV001760140	pathogenic	Type 2 diabetes mellitus		criteria provided, single submitter	clinical testing
GeneDx	RCV001385126	SCV001804628	pathogenic	not provided	2022-12-28	criteria provided, single submitter	clinical testing	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Identified in 6.53% of individuals with Wolfram syndrome (de Heredia et al., 2013); This variant is associated with the following publications: (PMID: 17568405, 20738327, 34758253, 15605410, 26875006, 32179840, 32141364, 21602428, 12955714, 27395765, 11161832, 15151504, 21446023, 22238590, 15277431, 33841295, 23429432)
Breda Genetics srl	RCV000004777	SCV001943369	pathogenic	Wolfram syndrome 1	2021-04-30	criteria provided, single submitter	clinical testing	The variant c.409_424dup (p.Val142Glyfs*110) in the WFS1 gene is reported as pathogenic for Wolfram syndrome 1 and WFS1-related spectrum disorders in ClinVar (Variation ID: 4519), and as pathogenic in the Global Variome shared LOVD database v.3.0. It creates a shift in the reading frame, which is predicted to result in a premature stop codon 110 amino acids downstream and in a truncated protein or protein loss due to nonsense-mediated messenger decay (NMD). The variant is reported with an estimated allele frequency of 0.0000439 in gnomAD exomes, with no homozygous individuals reported. According to the systematic review conducted by De Heredia et al. (2013) about disease-causing mutations in 412 patients with Wolfram syndrome, the c.409_424dup (p.Val142Glyfs*110) is present in about 6.53% of cases (PMID:23429432).
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV000004777	SCV002061668	pathogenic	Wolfram syndrome 1	2021-10-25	criteria provided, single submitter	clinical testing	PVS1, PM2, PM3
Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic	RCV000004777	SCV002605572	likely pathogenic	Wolfram syndrome 1		criteria provided, single submitter	research	Mutations in WFS1 gene are associated with Wolfram's syndrome, an autosomal recessive condition, which cause diabetes mellitus, diabetes insipidus, deafness and optic atrophy. rs1362648752 variant is also seen in patients with Diabetes Mellitus. However, the role of this particular variant is yet to be ascertained.
OMIM	RCV000004777	SCV000024953	pathogenic	Wolfram syndrome 1	2004-06-01	no assertion criteria provided	literature only