ClinVar Miner

Submissions for variant NM_006005.3(WFS1):c.2020G>A (p.Gly674Arg) (rs200672755)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000197395 SCV000252537 pathogenic not provided 2014-02-13 criteria provided, single submitter clinical testing p.Gly674Arg (GGG>AGG): c.2020 G>A in exon 8 of the WFS1 gene (NM_006005.3) The G674R missense mutation in the WFS1 gene has been reported previously in association with Wolfram syndrome (Khanim et al., 2001). The G674R mutation is a non-conservative amino acid substitution as these residues differ in polarity, charge, size and/or other properties and is more likely to impact secondary structure. This mutation occurs at a highly conserved position in the WFS1 protein, and other missense mutations at the same position (G674E, G674V) have been reported as pathogenic. Wofram syndrome is 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).
Genomic Research Center, Shahid Beheshti University of Medical Sciences RCV000625904 SCV000746483 likely pathogenic WFS1-Related Spectrum Disorders 2017-12-03 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000825499 SCV000966802 uncertain significance not specified 2018-04-10 criteria provided, single submitter clinical testing The p.Gly674Arg variant has been previously reported in an individual with Wolfr am syndrome and an individual with hearing loss (de Heredia 2013, Hakli 2014); h owever, this variant is also present in 0.02% (62/276372) of the total chromosom es in the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs200672755). Two missense variants at the same position (Gly674Glu and G ly674Val) have been reported to segregate in families with hearing loss (Cryns 2 002). Computational prediction tools and conservation analysis suggest that thi s variant may impact the protein, though this information is not predictive enou gh to determine pathogenicity. In summary, due to conflicting evidence, the clin ical significance of the p.Gly674Arg variant is uncertain. ACMG/AMP Criteria app lied: PP3; PM5; BS1_Supporting.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000197395 SCV001154167 likely pathogenic not provided 2018-11-01 criteria provided, single submitter clinical testing
Department of Otolaryngology – Head & Neck Surgery,Cochlear Implant Center RCV001375186 SCV001571792 likely pathogenic Hearing impairment 2021-04-12 criteria provided, single submitter clinical testing PS1_Strong, PM1_Moderate, PP3_Supporting
Constantin Polychronakos Laboratory,The Research Institute of the McGill University Health Centre RCV001175319 SCV001250637 pathogenic Diabetes mellitus no assertion criteria provided research PS1 PM2, PM5, PP3 PP5

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