Submissions for variant NM_006005.3(WFS1):c.728C>T (p.Ala243Val)

gnomAD frequency: 0.00012  dbSNP: rs147147660

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000732080	SCV000252518	likely benign	not provided	2021-01-07	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 25133958)
Eurofins Ntd Llc (ga)	RCV000732080	SCV000859985	uncertain significance	not provided	2018-02-27	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000765775	SCV000897164	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
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000825496	SCV000966799	uncertain significance	not specified	2018-09-04	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Benign. The p.Ala243Val var iant in WFS1 has been previously reported in an 81-year-old European individual with cerebellar ataxia who also harbored the c.1366C>T p.Arg456Cys variant in WF S1 (Fogel 2014). This variant has also been identified in 0.12% (38/30778) of So uth Asian chromosomes by gnomAD (http://gnomad.broadinstitute.org). Computationa l prediction tools and conservation analysis suggest that this variant may not i mpact the protein, though this information is not predictive enough to rule out pathogenicity. In summary, while the clinical significance of this variant is un certain, these data suggest that it is more likely to be benign. ACMG/AMP Criter ia applied: BS1_Supporting, BP4.
Illumina Laboratory Services, Illumina	RCV001157139	SCV001318686	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.
Illumina Laboratory Services, Illumina	RCV001157140	SCV001318687	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). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Personalized Diabetes Medicine Program, University of Maryland School of Medicine	RCV001174387	SCV001337525	uncertain significance	Monogenic diabetes	2018-05-18	criteria provided, single submitter	research	ACMG criteria: (PP3 (4 predictors), BP4 (5 predictors), Revel score 0.160; conflicting evidence, not using), variant found in 81-year old F w cerebellar ataxia but no DM noted (PMID: 25133958), no pathogenic variants in this exon in ClinVar= VUS
Labcorp Genetics (formerly Invitae), Labcorp	RCV000732080	SCV002336809	likely benign	not provided	2023-12-30	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002517279	SCV003739078	uncertain significance	Inborn genetic diseases	2022-08-26	criteria provided, single submitter	clinical testing	Unlikely to be causative of WFS1-related Wolfram syndrome (AD) Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.