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

gnomAD frequency: 0.00022  dbSNP: rs201064551

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham 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	2022-06-08	criteria provided, single submitter	clinical testing	Identified in an individual with hearing loss; no detailed clinical information or segregation information was provided for this individual (Chen et al., 2016); Identified in an individual with type II diabetes; no detailed clinical information or segregation information was provided for this individual (Awata et al., 2000); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 12955714, 31264968, 11317350, 31879078, 33046911, 10679252, 25388789, 27610647, 30174017)
Fulgent Genetics, Fulgent Genetics	RCV000515318	SCV000611534	uncertain significance	Cataract 41; Wolfram syndrome 1; Autosomal dominant nonsyndromic hearing loss 6; Type 2 diabetes mellitus; Wolfram-like syndrome	2017-05-23	criteria provided, single submitter	clinical testing
SIB Swiss Institute of Bioinformatics	RCV000677339	SCV000803617	uncertain significance	Autosomal dominant nonsyndromic hearing loss 6	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.
Illumina Laboratory Services, Illumina	RCV000677339	SCV001313297	uncertain significance	Autosomal dominant nonsyndromic hearing loss 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. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV001152091	SCV001313298	uncertain significance	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. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Invitae	RCV000767006	SCV001629615	likely benign	not provided	2024-01-22	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004534992	SCV004730114	likely benign	WFS1-related disorder	2020-03-03	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Laboratory of Prof. Karen Avraham, Tel Aviv University	RCV000677339	SCV005073823	likely pathogenic	Autosomal dominant nonsyndromic hearing loss 6	2024-06-13	criteria provided, single submitter	research	Likely pathogenic by Deafness Variation Databse based on PMID:10679252, 25388789