Submissions for variant NM_006005.3(WFS1):c.2327A>T (p.Glu776Val)

gnomAD frequency: 0.00354  dbSNP: rs56002719

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000152695	SCV000202071	benign	not specified	2012-05-07	criteria provided, single submitter	clinical testing	Glu776Val in Exon 08 of WFS1: This variant is not expected to have clinical sign ificance because it has been identified in 0.4% (31/7006) of European American c hromosomes from a broad population by the NHLBI Exome Sequencing Project (http:/ /evs.gs.washington.edu/EVS; dbSNP rs56002719).
GeneDx	RCV000658991	SCV000252554	benign	not provided	2020-03-04	criteria provided, single submitter	clinical testing	Identified in patients with Wolfram syndrome who harbored a second missense variant in the WFS1 gene in published literature but it is not known whether the variants occurred on the same (in cis) or on different (in trans) chromosomes (Smith et al., 2004; Astuti et al., 2017); This variant is associated with the following publications: (PMID: 21446023, 20981092, 24909696, 15277431, 28432734, 30245029, 31638168)
Illumina Laboratory Services, Illumina	RCV000351538	SCV000450670	likely benign	WFS1-Related Spectrum Disorders	2018-03-06	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
CeGaT Center for Human Genetics Tuebingen	RCV000658991	SCV000780794	likely benign	not provided	2023-05-01	criteria provided, single submitter	clinical testing	WFS1: BS2
Personalized Diabetes Medicine Program, University of Maryland School of Medicine	RCV000664094	SCV000787546	benign	Monogenic diabetes	2017-03-10	criteria provided, single submitter	research	ACMG Criteria:PP3 (10 predictors), BS1 (1.15% in ExAC Finnish population, 1 homo in ExAC), BS2 (39 cases and 42 controls in type2diabetesgenetics.org)
Eurofins Ntd Llc (ga)	RCV000152695	SCV000854880	benign	not specified	2017-11-21	criteria provided, single submitter	clinical testing
Invitae	RCV000658991	SCV001005785	benign	not provided	2024-01-29	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001157779	SCV001319381	benign	Autosomal dominant nonsyndromic hearing loss 6	2018-03-06	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000658991	SCV001477527	likely benign	not provided	2020-02-28	criteria provided, single submitter	clinical testing
INGEBI, INGEBI / CONICET	RCV001544546	SCV001763593	benign	Nonsyndromic genetic hearing loss	2021-07-15	criteria provided, single submitter	clinical testing	Based on ACMG/AMP guidelines and Hearing Loss Expert Panel specific criteria: The filter allele frequency of the c.2327A>T in WFS1 gene is 0,5% for european non-finnish and 1% for european finnish (calculatin with 95%CI) in gnomAD database, exceeding the treshold for dominant HL, meeting BA1. Computational analysis predicted a pathogenic effect of the mutation to the protein, REVEL= 0,98 (PP3). Our internal data demonstrated that the variant seggregated with the affected mother and grandother applying for PP1_Sup. However, there is a report in which the variant did not segregate with the pathology in a family (an unaffected sibling and father carried the mutation) meeting BS4. Taking into account the evidence: BA1, PP3, PP1_Sup and BS4 the vartiant is classified as Benign.
Genetic Services Laboratory, University of Chicago	RCV000152695	SCV002064900	likely benign	not specified	2021-10-21	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003917485	SCV004728747	likely benign	WFS1-related condition	2019-06-15	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).
Clinical Genetics, Academic Medical Center	RCV000658991	SCV001922760	likely benign	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000658991	SCV001955297	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000658991	SCV001965370	likely benign	not provided		no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000658991	SCV002036136	likely benign	not provided		no assertion criteria provided	clinical testing