Submissions for variant NM_006005.3(WFS1):c.1949_1950del (p.Tyr650fs)

dbSNP: rs1730930342

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV001195288	SCV001365598	pathogenic	Wolfram syndrome 1	2020-01-22	criteria provided, single submitter	clinical testing	The p.Tyr650CysfsX61 variant in WFS1 has been reported in six individuals with Wolfram syndrome, including three homozygotes and three compound heterozygotes (Domenech et al 2004; Gasparin et al 2009; Broad Rare Genomes Project). It was absent from large population studies. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 650 and leads to a premature termination codon 61 amino acids downstream. This termination codon occurs within the the last exon and is, therefore, likely to escape nonsense mediated decay (NMD) and result in a truncated protein. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Wolfram syndrome. ACMG/AMP Criteria applied: PVS1_Strong, PM3_Strong, PM2.
Invitae	RCV002561030	SCV003525595	pathogenic	not provided	2023-06-23	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: 929946). This variant is also known as T710X. This premature translational stop signal has been observed in individual(s) with autosomal recessive Wolfram syndrome (PMID: 15151504, 19042979). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Tyr650Cysfs*61) in the WFS1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 241 amino acid(s) of the WFS1 protein.
Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic	RCV001195288	SCV003802881	pathogenic	Wolfram syndrome 1		criteria provided, single submitter	research	Potent mutations in WFS1 gene are associated with Wolfram's syndrome, an autosomal recessive condition, which cause diabetes mellitus, diabetes insipidus, deafness and optic atrophy.However no sufficient evidence is found to ascertain the role of this particular variant rs1730930342 in Wolfram's syndrome yet.
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV003142122	SCV003807485	pathogenic	Cataract 41	2022-03-17	criteria provided, single submitter	clinical testing	ACMG classification criteria: PVS1 strong, PS4 supporting, PM2 moderated, PM3 strong
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV001195288	SCV003922214	pathogenic	Wolfram syndrome 1	2023-05-02	criteria provided, single submitter	curation	The heterozygous p.Tyr650CysfsTer61 variant in WFS1 was identified by our study, in the compound heterozygous state with a pathogenic variant (ClinVar Variation ID: 929945), in one individual with hearing impairment, blindness, cataracts, optic atrophy, enuresis, prostatitis, Type 1 diabetes mellitus, and seizures (Broad Institute Rare Genomes Project). The p.Tyr650CysfsTer61 variant in WFS1 has been previously reported in four unrelated individuals with Wolfram syndrome 1 (PMID: 19042979, PMID: 15151504) and segregated with disease in two affected relatives from one family (PMID: 19042979) but was absent from large population studies. Of these four previously reported individuals, two were homozygotes (PMID: 19042979, PMID: 15151504) and two were compound heterozygotes who carried reported pathogenic or likely pathogenic variants in trans (PMID: 19042979, ClinVar Variation ID: 2300477, 228420), which increases the likelihood that the p.Tyr650CysfsTer61 variant is pathogenic. This variant has also been reported in ClinVar (Variation ID: 929946) and has been interpreted as pathogenic by multiple submitters. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 650 and leads to a premature termination codon 61 amino acids downstream. This termination codon occurs within the last exon and is more likely to escape nonsense mediated decay (NMD) and result in a truncated protein. Loss of function of the WFS1 gene is an established disease mechanism in autosomal recessive Wolfram syndrome 1. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Wolfram syndrome 1. ACMG/AMP Criteria applied: PVS1_Strong, PM3_Strong, PM2_Supporting (Richards 2015).