Submissions for variant NM_006005.3(WFS1):c.2007T>G (p.Tyr669Ter)

gnomAD frequency: 0.00002  dbSNP: rs1443751733

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Mendelics	RCV000987412	SCV001136701	pathogenic	Wolfram syndrome 1	2019-05-28	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001858665	SCV002245791	pathogenic	not provided	2024-11-03	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Tyr669*) in the WFS1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 222 amino acid(s) of the WFS1 protein. This variant is present in population databases (no rsID available, gnomAD 0.008%). This premature translational stop signal has been observed in individual(s) with autosomal recessive Wolfram syndrome (PMID: 19042979). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 802052). This variant disrupts the p.Ala806 amino acid residue in WFS1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 24890733). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
DASA	RCV002221595	SCV002499423	likely pathogenic	WFS1-Related Spectrum Disorders	2022-04-10	criteria provided, single submitter	clinical testing	The c.2007T>G;p.(Tyr669*) variant creates a premature translational stop signal in the WFS1 gene without sufficient information about prediction of nonsense mediated mRNA decay (NMD) type change; it is present in a relevant exon to the transcript, and disrupts >10% of the protein product. PVS1_strong. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 802052; PMID: 31313226; 19042979; 28802351; 20738327) - PS4_supporting. The variant is present at low allele frequencies population databases (rs1443751733 – gnomAD 0.0001971%; ABraOM no frequency - https://abraom.ib.usp.br/) - PM2_supporting. The p.(Tyr669*) was detected in trans with a pathogenic variant (PMID: 19042979) - PM3_supporting. In summary, the currently available evidence indicates that the variant is likely pathogenic.
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV002252279	SCV002523194	likely pathogenic	See cases	2019-06-20	criteria provided, single submitter	clinical testing	ACMG classification criteria: PVS1, PM2
Fulgent Genetics, Fulgent Genetics	RCV002479153	SCV002777520	pathogenic	Cataract 41; Wolfram syndrome 1; Autosomal dominant nonsyndromic hearing loss 6; Type 2 diabetes mellitus; Wolfram-like syndrome	2024-03-19	criteria provided, single submitter	clinical testing
Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic	RCV000987412	SCV003802887	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 rs1443751733 in Wolfram's syndrome yet.