Submissions for variant NM_006005.3(WFS1):c.1371G>T (p.Arg457Ser)

gnomAD frequency: 0.00030  dbSNP: rs113446173

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
CeGaT Center for Human Genetics Tuebingen	RCV000488089	SCV000575393	uncertain significance	not provided	2017-03-01	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000603890	SCV000711250	uncertain significance	not specified	2016-06-20	criteria provided, single submitter	clinical testing	The p.Arg457Ser variant in WFS1 has been reported in one individual with atypica l Wolfram syndrome (Giuliano 2005). However, a variant affecting the remaining c opy of WFS1 was not identified in this individual, and a dominant family history of hearing loss was not described. This variant has been identified in 0.06% (3 9/66642) of European chromosomes by the Exome Aggregation Consortium (ExAC, http ://exac.broadinstitute.org; dbSNP rs113446173); however, its frequency is not hi gh enough to rule out a pathogenic role. Computational prediction tools and cons ervation analyses do not provide strong support for or against an impact to the protein. In summary, the clinical significance of this variant is uncertain.
Fulgent Genetics, Fulgent Genetics	RCV000765780	SCV000897169	uncertain significance	Cataract 41; Wolfram syndrome 1; Autosomal dominant nonsyndromic hearing loss 6; Type 2 diabetes mellitus; Wolfram-like syndrome	2018-10-31	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001153150	SCV001314412	likely benign	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. 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 Laboratory Services, Illumina	RCV001153151	SCV001314413	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.
Personalized Diabetes Medicine Program, University of Maryland School of Medicine	RCV001174421	SCV001337559	uncertain significance	Monogenic diabetes	2018-12-07	criteria provided, single submitter	research	ACMG criteria: BS2 (87 heterozygotes in gnomAD- too many for dominant Wolfram-like syndrome);Identified in 46-year old male with symptoms of Wolfram (late-onset though), authors suspect additional variant was not able to be detected (PMID: 15605410) but don't think we can use this as evidence= VUS (REVEL 0.665 + PP3/5 predictors + BP4/4 predictors= conflicting evidence, not using)
Molecular Medicine for Neurodegenerative and Neuromuscular Diseases Unit, IRCCS Fondazione Stella Maris	RCV001640297	SCV001519277	likely pathogenic	Spastic ataxia	2021-07-12	criteria provided, single submitter	research
Department of Otolaryngology – Head & Neck Surgery, Cochlear Implant Center	RCV001375054	SCV001571768	likely pathogenic	Hearing impairment	2021-04-12	criteria provided, single submitter	clinical testing	PS1_Strong, PM2_Moderate, PM5_Moderate, PP3_Supporting
Labcorp Genetics (formerly Invitae), Labcorp	RCV000488089	SCV002450397	likely benign	not provided	2023-12-11	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004530181	SCV004117054	uncertain significance	WFS1-related disorder	2022-12-21	criteria provided, single submitter	clinical testing	The WFS1 c.1371G>T variant is predicted to result in the amino acid substitution p.Arg457Ser. This variant was reported in the heterozygous state without a second potentially causative variant in an individual with Wolfram syndrome (Giuliano. 2005. PubMed ID: 15605410) and in an individual with hearing loss (Table S1, Sommen. 2016. PubMed ID: 27068579). This variant is reported in 0.061% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/4-6302893-G-T). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Ambry Genetics	RCV004020439	SCV004979909	uncertain significance	Inborn genetic diseases	2021-12-16	criteria provided, single submitter	clinical testing	The c.1371G>T (p.R457S) alteration is located in exon 8 (coding exon 7) of the WFS1 gene. This alteration results from a G to T substitution at nucleotide position 1371, causing the arginine (R) at amino acid position 457 to be replaced by a serine (S). Based on data from gnomAD, the T allele has an overall frequency of 0.03% (87/281,212) total alleles studied. The highest observed frequency was 0.06% (79/128,706) of European (non-Finnish) alleles. This amino acid position is not well conserved in available vertebrate species. The in silico prediction for this alteration is inconclusive. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Gharavi Laboratory, Columbia University	RCV000488089	SCV000920717	uncertain significance	not provided	2018-09-16	no assertion criteria provided	research
Clinical Genetics, Academic Medical Center	RCV000488089	SCV001922369	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000488089	SCV001963934	uncertain significance	not provided		no assertion criteria provided	clinical testing