ClinVar Miner

Submissions for variant NM_006005.3(WFS1):c.911_914dupTTGA (p.Met306Terfs) (rs863224264)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000197607 SCV000252549 likely pathogenic not provided 2018-09-14 criteria provided, single submitter clinical testing The c.911_914dupTTGA variant in the WFS1 gene has been reported previously in an individual with Wolfram syndrome who also harbored a nonsense variant; however, it is unclear if parental studies were performed to determine the phase of these two variants (Astuti et al., 2017). The c.911_914dupTTGA variant causes a frameshift which changes Methionine 306 to a premature Stop codon at position 306 of the new reading frame, denoted p.Met306Ter. This variant is predicted to cause loss of normal protein function either through protein truncation where the last 585 amino acids are lost. The c.911_914dupTTGA variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). We interpret c.911_914dupTTGA as a likely pathogenic variant.
Illumina Clinical Services Laboratory,Illumina RCV000778737 SCV000915095 uncertain significance WFS1-Related Spectrum Disorders 2016-12-22 criteria provided, single submitter clinical testing The WFS1 c.911_914dupTTGA (p.Met306Ter) variant results in a frameshift and is predicted to result in premature termination of the protein. It was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018) and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score for this variant, it could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene and cDNA change, and amino acid change. No publications were found based on this search. Due to the potential impact of frameshift variants and the lack of clarifying evidence, this variant is classified as a variant of unknown significance but suspicious for pathogenicity for WFS1-related spectrum disorders.

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