Submissions for variant NM_006005.3(WFS1):c.1230_1233del (p.Val412fs)

dbSNP: rs760337383

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000494474	SCV000582399	pathogenic	not provided	2022-07-18	criteria provided, single submitter	clinical testing	Frameshift variant predicted to result in protein truncation in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 20972738, 20738327, 27412528, 18566338, 29728875, 26025012, 11295831, 19042979, 12955714, 15605410, 23845777, 22238590, 29183106, 31600780, 32005694, 31589614, 34356170)
Illumina Laboratory Services, Illumina	RCV000778738	SCV000915096	pathogenic	WFS1-Related Spectrum Disorders	2018-11-02	criteria provided, single submitter	clinical testing	The WFS1 c.1230_1233delCTCT (p.Val412SerfsTer29) variant results in a frameshift and is predicted to result in premature termination of the protein. Across a selection of the available literature, the p.Val412SerfsTer29 variant, also known as c.1228_1231delCTCT and c.1234_1237delGTCT, has been identified in a homozygous state in 10 individuals and in a compound heterozygous state in 19 individuals, all of whom were diagnosed with Wolfram syndrome (Giuliano et al. 2005; d'Annunzio et al. 2008; Gasparin et al. 2009; Chaussenot et al. 2011; Sobhani et al. 2013; Aloi et al. 2013; Bischoff et al. 2015; Pedroso et al. 2015). To date, this variant has not been reported in association with autosomal dominant phenotypes. This variant was absent from 200 control chromosomes (Gasparin et al. 2009; Aloi et al. 2013) and is reported at a frequency of 0.00005 in the European (non-Finnish) population of the Exome Aggregation Consortium. Based on the collective evidence and the potential impact of frameshift variants, the p. Val412SerfsTer29 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.
Molecular Endocrinology Laboratory, Christian Medical College	RCV001672804	SCV001890913	pathogenic	Wolfram syndrome 1		criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000494474	SCV002232144	pathogenic	not provided	2023-12-25	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Val412Serfs*29) in the WFS1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 479 amino acid(s) of the WFS1 protein. This variant is present in population databases (rs760337383, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with autosomal recessive Wolfram syndrome (PMID: 11295831, 15605410, 22238590, 31600780). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 429753). For these reasons, this variant has been classified as Pathogenic.
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV002252138	SCV002523050	pathogenic	See cases	2024-01-31	criteria provided, single submitter	clinical testing	ACMG classification criteria: PVS1_strong, PM2_supporting, PM3_very strong, PP4_supporting
Fulgent Genetics, Fulgent Genetics	RCV002481565	SCV002777856	pathogenic	Cataract 41; Wolfram syndrome 1; Autosomal dominant nonsyndromic hearing loss 6; Type 2 diabetes mellitus; Wolfram-like syndrome	2021-12-24	criteria provided, single submitter	clinical testing
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV001672804	SCV003807743	pathogenic	Wolfram syndrome 1	2024-02-22	criteria provided, single submitter	clinical testing	ACMG classification criteria: PVS1 strong, PM3 very strong, PM2 supporting, PP4 supporting.
Revvity Omics, Revvity	RCV000494474	SCV003821850	pathogenic	not provided	2022-12-08	criteria provided, single submitter	clinical testing
Neuberg Centre For Genomic Medicine, NCGM	RCV001672804	SCV004047052	pathogenic	Wolfram syndrome 1		criteria provided, single submitter	clinical testing	The WFS1 c.1230_1233del (p.Val412SerfsTer29) variant has been reported in homozygous state in individuals affected with Wolfram syndrome 1 (Tessa et al., 2001). This variant is reported with the allele frequency (0.003536%) in the gnomad and novel in 1000 genome database. It has been submitted to ClinVar as Pathogenic. This variant causes a frameshift starting with codon Valine 412, changes this amino acid to Serine residue, and creates a premature Stop codon at position 29 of the new reading frame, denoted p.Val412SerfsTer29. This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants have been previously reported to be disease causing. For these reasons, this variant has been classified as Pathogenic.
PreventionGenetics, part of Exact Sciences	RCV004535551	SCV004118215	pathogenic	WFS1-related disorder	2023-09-25	criteria provided, single submitter	clinical testing	The WFS1 c.1230_1233delCTCT variant is predicted to result in a frameshift and premature protein termination (p.Val412Serfs*29). This variant has been reported to be causative for autosomal recessive Wolfram syndrome (Reported as 1387delCTCT in Tessa et al. 2001. PubMed ID: 11295831; Marshall et al. 2013. PubMed ID: 23981289). It is interpreted as pathogenic by multiple independent submitters to the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/429753). This variant is reported in 0.011% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/4-6302749-GCTCT-G). Frameshift variants in WFS1 are a commonly documented cause of Wolfram syndrome (Human Gene Mutation Database, http://www.hgmd.cf.ac.uk/ac/index.php). In summary, this variant is interpreted as pathogenic.
OMIM	RCV001672804	SCV000044808	pathogenic	Wolfram syndrome 1	2001-04-01	no assertion criteria provided	literature only
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000494474	SCV002035127	pathogenic	not provided		no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000494474	SCV002037029	pathogenic	not provided		no assertion criteria provided	clinical testing