Submissions for variant NM_006005.3(WFS1):c.2254G>T (p.Glu752Ter)

gnomAD frequency: 0.00002  dbSNP: rs201239579

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000195490	SCV000252542	pathogenic	not provided	2017-05-05	criteria provided, single submitter	clinical testing	The E752X nonsense variant has been reported previously in two patients diagnosed with Wolfram syndrome (Hardy et al. 1999). In one patient, a frameshift variant and a missense variant were also identified in the WFS1 gene, while in the second patient no other variants in WFS1 were identified (Hardy et al., 1999). E752X was not observed with any significant frequency in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. This variant is predicted to cause loss of normal protein function through protein truncation. In summary, we interpret this variant as pathogenic.
Molecular Diagnostics Laboratory, M Health Fairview: University of Minnesota	RCV001730586	SCV001981523	likely pathogenic	Wolfram-like syndrome	2021-08-25	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000195490	SCV002065919	likely pathogenic	not provided	2022-01-20	criteria provided, single submitter	clinical testing	DNA sequence analysis of the WFS1 gene demonstrated a sequence change,c.2254G>T , which results in the creation of a premature stop codon at amino acid position 752, p.Glu752*. This pathogenic sequence change is predicted to result in an abnormal transcript, which may be degraded, or may lead to the production of a truncated WFS1 protein with potentially abnormal function. This sequence change has been described in the gnomAD database in one heterozygous individual which corresponds to a population frequency of 0.00041% (dbSNP rs201239579). This sequence change has been reported previously in two individuals with Wolfram syndrome (PMID: 10521293). In one individual, a frameshift variant and a missense variant were also identified in the WFS1 gene, while in the second individual no other variants in WFS1 were identified (PMID: 10521293).
Invitae	RCV000195490	SCV003525499	pathogenic	not provided	2023-12-21	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Glu752*) in the WFS1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 139 amino acid(s) of the WFS1 protein. This variant is present in population databases (rs201239579, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with Wolfram syndrome (PMID: 15277431, 23981289). ClinVar contains an entry for this variant (Variation ID: 215399). For these reasons, this variant has been classified as Pathogenic.