ClinVar Miner

Submissions for variant NM_006005.3(WFS1):c.2195G>A (p.Arg732His) (rs149013740)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000197209 SCV000340155 uncertain significance not provided 2016-03-28 criteria provided, single submitter clinical testing
GeneDx RCV000197209 SCV000252540 likely pathogenic not provided 2014-05-27 criteria provided, single submitter clinical testing p.Arg732His (CGC>CAC): c.2195 G>A in exon 8 of the WFS1 gene (NM_006005.3) A R732H missense change that is likely disease-causing has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The R732H variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. However, this change occurs at a highly conserved position in the WFS1 protein, and missense mutations at nearby positions (D729N, G736R, G736S, E737K) have been reported as WFS1-disease associated mutations, supporting the functional importance of this region of the protein. Furthermore, multiple in-silico analysis models predict that R732H is damaging to the WFS1 protein. Therefore, R732H is a strong candidate for a disease-causing mutation, however the possibility that it is a benign variant cannot be excluded. Mutations in the WFS1 gene are most often associated with Wofram syndrome; an autosomal recessive neurodegenerative disorder characterized by onset of diabetes mellitus and optic atrophy before age 15 years and is usually associated with sensorineural hearing loss, progressive neurological abnormalities, and other endocrine abnormalities (Tranebjaerg et al., 2009). Autosomal dominant inheritance of WFS1 mutations have been reported in association with Wolfram syndrome-like disease in two families with low-frequency sensorineural hearing loss, diabetes mellitus, psychiatric illness and in one family, optic atrophy (Tranebjaerg et al., 2009). The variant is found in MITONUC-MITOP panel(s).

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