ClinVar Miner

Submissions for variant NM_006005.3(WFS1):c.2452C>T (p.Arg818Cys) (rs35932623)

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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Genetic Services Laboratory, University of Chicago RCV000118865 SCV000153520 benign not specified 2013-03-27 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000118865 SCV000205099 benign not specified 2015-04-16 criteria provided, single submitter clinical testing p.Arg818Cys in exon 8 of WFS1: This variant is not expected to have clinical sig nificance because it has been identified in 0.8% (129/15874) of South Asian chro mosomes including 1 homozygote by the Exome Aggregation Consortium (ExAC, http:/ /exac.broadinstitute.org; dbSNP rs35932623).
GeneDx RCV000118865 SCV000252544 uncertain significance not specified 2016-07-05 criteria provided, single submitter clinical testing The R818C variant in the WFS1 gene was initially reported in the homozygous state in two siblings with Wolfram syndrome who were reported to also harbor the A4136G mitochondrial variant associated with Leber hereditary optic neuropathy (LHON) (Gomez-Zaera et al., 2001). In that family, R818C was inherited from consanguineous parents who were heterozygous for this variant, with the father noted to have deafness and the mother with diabetes mellitus (Gomez-Zaera et al., 2001). Domenech et al. (2004) also detected the R818C variant on both WFS1 alleles in an individual with Wolfram syndrome. The R818C variant was identified in the heterozygous state in another individual who was also homozygous for an in-frame insertion of three amino acids in the WFS1 gene (Smith et al., 2004). The R818C variant was incidentally identified in the diabetic father of a proband with Wolfram syndrome, though the proband had not inherited this variant (Smith et al., 2004).The NHLBI Exome Sequencing Project reports R818C was observed in 57/8600 alleles (0.66%) from individuals of European ancestry; no individuals within this control group were reported as homozygous for this variant. The R818C variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved in mammals and in silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, we interpret R818C as a variant of uncertain significance.
PreventionGenetics,PreventionGenetics RCV000118865 SCV000311327 likely benign not specified criteria provided, single submitter clinical testing
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000118865 SCV000331434 likely benign not specified 2015-12-21 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000336052 SCV000450687 likely benign WFS1-Related Spectrum Disorders 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Illumina Clinical Services Laboratory,Illumina RCV000403034 SCV000450688 likely benign Autosomal dominant nonsyndromic deafness 6 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Personalized Diabetes Medicine Program,University of Maryland School of Medicine RCV000445373 SCV000537022 uncertain significance Monogenic diabetes 2015-07-31 criteria provided, single submitter research ACMG Criteria: PP3, PP5 (PMID:21446023), BS2, BP6
CeGaT Praxis fuer Humangenetik Tuebingen RCV000487646 SCV000575400 uncertain significance not provided 2017-08-01 criteria provided, single submitter clinical testing
Invitae RCV000487646 SCV001005999 benign not provided 2020-12-03 criteria provided, single submitter clinical testing
Mendelics RCV000987413 SCV001136703 benign Wolfram syndrome 1 2019-05-28 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001282325 SCV001158286 likely benign none provided 2019-09-27 criteria provided, single submitter clinical testing

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