Submissions for variant NM_006005.3(WFS1):c.2189G>A (p.Trp730Ter)

dbSNP: rs760171298

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000498226	SCV000589799	likely pathogenic	not provided	2022-11-09	criteria provided, single submitter	clinical testing	Nonsense 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; Not observed at significant frequency in large population cohorts (gnomAD); Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 23981289, 15277431)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000498226	SCV002197929	pathogenic	not provided	2023-09-01	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Trp730*) in the WFS1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 161 amino acid(s) of the WFS1 protein. This premature translational stop signal has been observed in individual(s) with autosomal recessive Wolfram syndrome (Invitae). ClinVar contains an entry for this variant (Variation ID: 432114). This variant disrupts a region of the WFS1 protein in which other variant(s) (p.Glu752*) have been determined to be pathogenic (PMID: 15277431, 23981289). 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. This variant is present in population databases (rs760171298, gnomAD 0.003%).
Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic	RCV003126758	SCV003802908	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 rs760171298 in Wolfram's syndrome yet.