Submissions for variant NM_006005.3(WFS1):c.1957C>T (p.Arg653Cys) (rs201064551)

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Total submissions: 4

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Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine	RCV000155347	SCV000205033	uncertain significance	not specified	2014-02-01	criteria provided, single submitter	clinical testing	The Arg653Cys variant in WFS1 has not been previously reported in individuals wi th hearing loss. This variant has been identified in 0.035% (3/8600) of European American chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washi ngton.edu/EVS/; dbSNP rs201064551). Computational analyses (biochemical amino ac id properties, conservation, AlignGVGD, PolyPhen2, and SIFT) do not provide stro ng support for or against an impact to the protein. In summary, additional infor mation is needed to determine the clinical significance of this variant.
GeneDx	RCV000767006	SCV000252535	uncertain significance	not provided	2012-12-06	criteria provided, single submitter	clinical testing	p.Arg653Cys (CGC>TGC):c.1957 C>T in exon 8 of the WFS1 gene (NM_006005.3). The R456H missense substitution in the WFS1 gene has been published in association with type 1 diabetes in a Japanese population where it was found at a significantly increased frequency in patients with type 1 diabetes compared to a control group (Awata et al., 2000). The amino acid change is conservative in that both Arginine and Histidine are positively charged amino acids. This change occurs at a position in the WFS1 protein that is highly conserved. Therefore, based on the currently available information, it is unclear whether R456H is a disease-causing mutation or a rare benign variant. The variant is found in MITONUC-MITOP panel(s).
Fulgent Genetics,Fulgent Genetics	RCV000515318	SCV000611534	uncertain significance	Cataract 41; Diabetes mellitus AND insipidus with optic atrophy AND deafness; WFS1-Related Disorders; Diabetes mellitus type 2; Wolfram-like syndrome, autosomal dominant	2017-05-23	criteria provided, single submitter	clinical testing
SIB Swiss Institute of Bioinformatics	RCV000677339	SCV000803617	uncertain significance	WFS1-Related Disorders	2018-05-31	criteria provided, single submitter	curation	This variant is interpreted as a Uncertain Significance - Conflicting Evidence, for Deafness, in Autosomal Dominant manner. The following ACMG Tag(s) were applied: PP3 => Multiple lines of computational evidence support a deleterious effect on the gene or gene product. PP1 => Cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease (PMID:25388789). BS1 => Allele frequency is greater than expected for disorder.

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