Submissions for variant NM_006005.3(WFS1):c.2039A>C (p.Glu680Ala)

gnomAD frequency: 0.00050  dbSNP: rs144840779

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000725856	SCV000339960	uncertain significance	not provided	2018-09-07	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000354766	SCV000711254	uncertain significance	not specified	2017-12-21	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Benign. The p.Glu680Ala var iant in WFS1 has not been previously reported in individuals with hearing loss, but has been identified in 0.21% (51/24020) of African chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs1448407 79). Although this variant has been seen in the general population, its frequenc y is not high enough to rule out a pathogenic role. Computational prediction too ls and conservation analysis suggest that the p.Glu680Ala variant may not impact the protein, though this information is not predictive enough to rule out patho genicity. In summary, while the clinical significance of the p.Glu680Ala variant is uncertain, available data suggest that it is more likely to be benign. ACMG/ AMP Criteria applied: BP4.
Personalized Diabetes Medicine Program, University of Maryland School of Medicine	RCV000664092	SCV000787544	uncertain significance	Monogenic diabetes	2017-06-26	criteria provided, single submitter	research	ACMG Criteria:PP3 (9 predictors) NOTE: Emory calls VUS in ClinVar 4/2016
Labcorp Genetics (formerly Invitae), Labcorp	RCV000725856	SCV001092077	likely benign	not provided	2023-12-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000725856	SCV001768360	uncertain significance	not provided	2021-08-24	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
New York Genome Center	RCV002467719	SCV002764488	uncertain significance	Wolfram syndrome 1; Wolfram-like syndrome	2020-11-30	criteria provided, single submitter	clinical testing	The c.2039A>C (p.Glu680Ala) variant identified in the WFS1 gene substitutes a well conserved Glutamic Acid for Alanine at amino acid 680/891 (exon 8/8). This variant is found in gnomADv3.0 (73 heterozygotes, 0 homozygotes; allele frequency: 4.80e-4). In silico algorithms predict this variant to be Damaging (SIFT; score:0.018) and Pathogenic (REVEL; score:0.681) to the function of the canonical transcript. The c.2039A>C (p.Glu680Ala) variant is reported in ClinVar as a Variant of Uncertain Significance (3 entries) and as Likely Benign (1 entry) (VarID:286507). To our current knowledge this variant has not been previously reported in affected individuals in the literature. Given the lack of compelling evidence for its pathogenicity, thec.2039A>C (p.Glu680Ala) variant identified in the WFS1 gene is reported as a Variant of Uncertain Significance.
Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic	RCV003126663	SCV003802915	uncertain risk allele	Wolfram syndrome 1		criteria provided, single submitter	research	Potent mutations in WFS1 gene are associated with Wolfram's syndrome, an autosomal recessive condition, which cause diabetes mellitus, diabetes insipidus, deafness and optic atrophy.However no sufficient evidence is found to ascertain the role of this particular variant rs144840779 in Wolfram's syndrome yet.
PreventionGenetics, part of Exact Sciences	RCV004543084	SCV004787473	likely benign	WFS1-related disorder	2023-01-13	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).