ClinVar Miner

Submissions for variant NM_001145853.1(WFS1):c.2648_2651del (p.Phe883fs) (rs797045076)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Baylor Genetics RCV000191146 SCV000245555 pathogenic Wolfram syndrome 1 2015-05-04 criteria provided, single submitter clinical testing This variant has been previously reported as disease-causing and was found once in our laboratory in trans with a missense variant [C755R] in a 38-year-old female with Asperger, ataxia, optic atrophy, progressive vision impairment, spastic bladder, chronic fatigue, irregular menses. Variant is pathogenic in recessive state. Found once in our laboratory heterozygous in a 48-year-old male with type 2 diabetes and family history of sudden death.
GeneDx RCV000200365 SCV000252562 likely pathogenic not provided 2017-03-02 criteria provided, single submitter clinical testing The c.2648_2651delTCTT variant in the WFS1 gene has been reported previously in the homozygous state or in the presence of another WFS1 variant in multiple unrelated individuals with autosomal recessive Wolfram syndrome (Hardy et al., 1999). The c.2648_2651delTCTT variant causes a frameshift starting with codon Phenylalanine 883, changes this amino acid to a Serine residue and creates a premature Stop codon at position 68 of the new reading frame, denoted p.Phe883SerfsX68. This frameshift variant replaces the typical last 8 amino acid residues in the protein with 67 different amino acid residues. This change is expected to alter the normal structure and function of the resultant protein. The c.2648_2651delTCTT variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). We interpret c.2648_2651delTCTT as a strong candidate for a pathogenic variant; however, the possibility it may be a rare benign variant cannot be completely excluded.
Invitae RCV000200365 SCV001409808 pathogenic not provided 2019-10-30 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the WFS1 gene (p.Phe883Serfs*68). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 8 amino acids of the WFS1 protein and extend it by an additional 60 amino acids. This variant is present in population databases (rs772120569, ExAC 0.01%). This variant has been reported in individuals affected with autosomal recessive Wolfram syndrome (PMID: 10521293, 11260218, 16151413, 28432734), including at least two individuals who were homozygous for this variant. It is also known as 2646-2649del in the literature. ClinVar contains an entry for this variant (Variation ID: 209207). For these reasons, this variant has been classified as Pathogenic.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000200365 SCV001500780 pathogenic not provided 2020-07-01 criteria provided, single submitter clinical testing
OMIM RCV000191146 SCV000024952 pathogenic Wolfram syndrome 1 2001-02-01 no assertion criteria provided literature only

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