Submissions for variant NM_006005.3(WFS1):c.1597C>T (p.Pro533Ser)

gnomAD frequency: 0.00076  dbSNP: rs146132083

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000724541	SCV000169821	likely pathogenic	not provided	2024-08-26	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 12955714, 11920861, 28432734, 20738327, 26435059, 31264968, 24875298, 33841295, 34746052, 30180840, 31765440, 35469785, 26875006, 35472603, OrssaudC2024[preprint])
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000155342	SCV000205028	uncertain significance	not specified	2018-06-12	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Benign. The p.Pro533Ser var iant in WFS1 has been reported in 1 individual with Wolfram Syndrome and 1 indiv idual with post-lingual mild sensorineural hearing loss, but a second variant in WFS1 was not identified in either case (Prince 2012, LMM data). This variant wa s identified in an unaffected parent, suggesting that it would not cause the dom inant form of disease. This variant has also been identified in 0.12% (82/67552) of European chromosomes by the Exome Aggregation Consortium (http://exac.broadi nstitute.org; dbSNP rs146132083), though this frequency is not high enough to ru le out a pathogenic role. Computational prediction tools and conservation analys is suggest that the Pro533Ser variant may impact the protein, though this inform ation is not predictive enough to determine pathogenicity. In summary, while the clinical significance of the p.Pro533Ser variant is uncertain, its frequency in the general population suggests that it is more likely to be benign. ACMG/AMP c riteria applied: BS1_Supporting.
Eurofins Ntd Llc (ga)	RCV000724541	SCV000232700	uncertain significance	not provided	2018-07-03	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000724541	SCV000892392	uncertain significance	not provided	2024-02-01	criteria provided, single submitter	clinical testing	WFS1: PP3
Illumina Laboratory Services, Illumina	RCV001151986	SCV001313178	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.
Illumina Laboratory Services, Illumina	RCV001151987	SCV001313179	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000724541	SCV001557511	uncertain significance	not provided	2025-01-31	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 533 of the WFS1 protein (p.Pro533Ser). This variant is present in population databases (rs146132083, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with Wolfram syndrome (PMID: 26875006, 28432734, 31264968, 33841295, 35469785). ClinVar contains an entry for this variant (Variation ID: 137914). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt WFS1 protein function with a positive predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics	RCV002514675	SCV003539792	uncertain significance	Inborn genetic diseases	2022-08-05	criteria provided, single submitter	clinical testing	The c.1597C>T (p.P533S) alteration is located in exon 8 (coding exon 7) of the WFS1 gene. This alteration results from a C to T substitution at nucleotide position 1597, causing the proline (P) at amino acid position 533 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV000724541	SCV004244503	uncertain significance	not provided	2023-11-20	criteria provided, single submitter	clinical testing	PM3_Strong, BS1, PP3
Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg	RCV004815195	SCV005069543	uncertain significance	Optic atrophy	2023-01-01	criteria provided, single submitter	clinical testing
Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg	RCV004815194	SCV005073442	uncertain significance	Retinal dystrophy	2023-01-01	criteria provided, single submitter	clinical testing
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre	RCV004820834	SCV005442064	uncertain significance	Wolfram syndrome 1	2024-12-19	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV005025204	SCV005660264	uncertain significance	Cataract 41; Wolfram syndrome 1; Autosomal dominant nonsyndromic hearing loss 6; Type 2 diabetes mellitus; Wolfram-like syndrome	2024-06-05	criteria provided, single submitter	clinical testing
Personalized Diabetes Medicine Program, University of Maryland School of Medicine	RCV000664090	SCV000787542	likely benign	Monogenic diabetes	2018-01-12	flagged submission	research	ACMG criteria: PP3 (10 predictors), BS2 ( 8 controls and 5 cases in T2DM), BP6 (GeneDx says benign), NOTE: Emory and Partners call it VUS, (previously reported in patient with optic atrophy, hearing loss, neurogenic bladder, but no diabetes), PMID 28432734)=likely benign
PreventionGenetics, part of Exact Sciences	RCV004528845	SCV004105134	likely pathogenic	WFS1-related disorder	2024-09-13	no assertion criteria provided	clinical testing	The WFS1 c.1597C>T variant is predicted to result in the amino acid substitution p.Pro533Ser. This variant has been reported along with a second WFS1 variant in individuals with Wolfram syndrome and/or optic atrophy (Table S1 in Majander et al. 2016. PubMed ID: 26875006; Table S2 in Charif et al. 2021. PubMed ID: 33841295). Additionally, here at PreventionGenetics, this variant has been detected in trans with a pathogenic variant in an individual undergoing testing for optic atrophy (internal data). This variant is reported in 0.15% of alleles in individuals of European (Non-Finnish) descent in gnomAD, indicating this variant is relatively common. This variant is interpreted as likely pathogenic.