Submissions for variant NM_006005.3(WFS1):c.1672C>T (p.Arg558Cys)

gnomAD frequency: 0.00035  dbSNP: rs199946797

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000255189	SCV000232696	likely pathogenic	not provided	2015-01-29	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000599628	SCV000271294	uncertain significance	not specified	2017-09-05	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Pathogenic. The p.Arg558Cys variant in WFS1 has been previously reported in the homozygous or compound hete rozygous state in 5 individuals with Wolfram syndrome, at least 3 of whom were r eported to have late onset disease (Cano 2007, Chaussenot 2011, Lieber 2012, Cha ussenot 2015, Astuti 2017, Oakley 2017). It has also been identified in at least 2 individuals with nonsyndromic optic atrophy and 1 individual with progressive cerebellar ataxia (Fogel 2014, Grenier 2016, Sharma 2017). Additionally, our la boratory has identified the p.Arg558Cys variant in the heterozygous state in 2 i ndividuals with apparently nonsyndromic hearing loss, 1 of whom had an alternate explanation for their hearing loss. In vitro functional studies and in silico p rediction tools provide some evidence that the variant may impact protein functi on (Qian 2015, Sharma 2017); however, these types of assays may not accurately r epresent biological function. This variant has been identified in 1.4% (140/1015 0) of Ashkenazi Jewish chromosomes by the Genome Aggregation Database, including 1 homozygous individual (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs1999 46797). It should be noted that the gnomAD database may include individuals with late onset or adult disease such as diabetes mellitus and psychiatric disorders (http://gnomad.broadinstitute.org/about). In summary, while there is some suspi cion for a pathogenic role, because of its high frequency in the Ashkenazi Jewis h population and limited functional data, the clinical significance of this vari ant is uncertain.
GeneDx	RCV000255189	SCV000322006	pathogenic	not provided	2022-07-26	criteria provided, single submitter	clinical testing	Observed in apparent homozygous state in multiple patients with early-onset diabetes with or without other features of Wolfram syndrome, supporting the conclusion that p.(R558C) causes a mild form of Wolfram syndrome, with later onset of diabetes (17.8 +/- 8.3 years) and absence of optic atrophy in most homozygous individuals of Ashkenazi Jewish ancestry (Bansal et al., 2018); Observed in heterozygous state in an individual with ataxia and in an individual with familial schizophrenia (Fogel et al., 2014; Torres et al., 2001), however it is unclear whether the variant contributed to these individuals' phenotypes; In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 25133958, 21446023, 28432734, 24890733, 31264968, 27395765, 26435059, 17568405, 30245029, 22226368, 30957632, 12754709, 15277431, 19344068, 32518033, 32335055, 33046911, 34556497, 31980526, 33763535, 11244483, 30014265, 34746052, 35018440, 35206658, Kitamura2021[preprint], 33538814, 35602877, 29207974)
Genetic Services Laboratory, University of Chicago	RCV000501459	SCV000597980	likely pathogenic	Wolfram syndrome	2016-05-11	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000778739	SCV000915097	pathogenic	WFS1-Related Spectrum Disorders	2018-10-10	criteria provided, single submitter	clinical testing	The WFS1 c.1672C>T (p.Arg558Cys) missense variant has been reported in at least seven studies and is found in a total of 15 individuals with Wolfram syndrome, including in a homozygous state in at least ten individuals, in a compound heterozygous state in two, and in a heterozygous state in three individuals (Cano et al. 2007; Ganie et al. 2009; Chaussenot et al. 2011; Lieber et al. 2012; Chaussenot et al. 2015; Grenier et al. 2016; Bansal et al. 2018). The variant was also reported in a heterozygous state in one individual with schizophrenia (Torres et al. 2001) and in another individual with cerebellar ataxia (Fogel et al. 2014). The p.Arg558Cys is identified with a very mild phenotype that authors indicate may be difficult to diagnose clinically (Bansal et al. 2018). The p.Arg558Cys variant was found in 58 alleles from 2589 control sample and is reported at a frequency of 0.00084 in the European (non-Finnish) population of the Exome Aggregation Consortium and 0.013790 in the Ashkenazi Jewish population of the Genome Aggregation Database. Based on the evidence, the p.Arg558Cys variant is classified as pathogenic for WFS1-related spectrum disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000255189	SCV001559490	pathogenic	not provided	2024-01-17	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 558 of the WFS1 protein (p.Arg558Cys). This variant is present in population databases (rs199946797, gnomAD 1.4%), including at least one homozygous and/or hemizygous individual. This missense change has been observed in individual(s) with clinical features of Wolfram syndrome (PMID: 17568405, 21446023, 23596069, 27395765, 28432734, 29207974, 30014265, 30957632, 33763535, 34404380). It is commonly reported in individuals of Ashkenazi Jewish ancestry (PMID: 30014265). This variant might be associated with later onset or milder phenotypes. ClinVar contains an entry for this variant (Variation ID: 198835). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on WFS1 protein function. This variant disrupts the p.Arg558 amino acid residue in WFS1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15277431, 31567480). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Molecular Endocrinology Laboratory, Christian Medical College	RCV001706152	SCV001890919	likely pathogenic	Wolfram syndrome 1		criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000255189	SCV003823772	uncertain significance	not provided	2021-03-29	criteria provided, single submitter	clinical testing
New York Genome Center	RCV003227696	SCV003925122	uncertain significance	Type 2 diabetes mellitus	2022-06-10	criteria provided, single submitter	clinical testing	The c.1672C>T (p.Arg558Cys) missense variant identified in WFS1 has been reported in homozygous as well as in compound heterozygous states in individuals affected with autosomal recessive Wolfram syndrome [PMID: 30957632, 17568405, 21446023], reported as heterozygous in individuals affected with autosomal dominant Wolfram-like syndrome [PMID: 27395765], in three individuals in a cohort of 1019 patients with type 1 diabetes [PMID:31264968] and in a single patient in a large cohort of type 2 diabetes patients [PMID:33046911]. It was also reported as a variant of uncertain significance in an individual affected with ataxia and polyneuropathy and in an individual affected with familial schizophrenia [PMID: 25133958, 11244483]. The variant has 0.0003284 allele frequency in the gnomAD(v3) database (50 out of 152262 heterozygous alleles, no homozygotes), 0.0006277 allele frequency in the gnomAD(v2) database (177 out of 281960 heterozygous alleles,1 homozygote) and 0.01341 allele frequency in the Ashkenazi Jewish subpopulation represented in gnomAD(v2) database (139 out of 10366 heterozygous alleles, 1 homozygous allele). Multiple independent laboratories have reported this variant in the ClinVar database with conflicting interpretations of pathogenicity for WFS1-related disorders [Variation ID: 198835; Pathogenic = 2, Likely pathogenic = 2, and Uncertain significance = 3]. This variant replaces highly conserved arginine residue [Arg558] and is predicted deleterious by multiple in silico tools (CADD score = 32, REVEL score = 0.816). Based on the available evidence,the heterozygous c.1672C>T (p.Arg558Cys) missense variant identified in the WFS1 gene is reported as a Variant of Uncertain Significance
New York Genome Center	RCV001706152	SCV004046580	pathogenic	Wolfram syndrome 1	2022-10-25	criteria provided, single submitter	clinical testing	The c.1672C>T variant identified in WFS1 has been reported in homozygous as well as compound heterozygous states in at least 20 individuals with late-onset Wolfram syndrome [PMID: 17568405, 21446023, 22226368, 24890733, 30014265, 30957632, 33763535], and it has been deposited in ClinVar [ClinVarID:198835]. The c.1672C>T is observed in 218 alleles (~0.05% minor allele frequency (MAF) with 1 homozygote) in population databases (gnomAD v2.1.1 and v3.1.2), with having >1% MAF in individuals of Ashkenazi Jewish ancestry suggesting it might be a founder variant in that population. Of note, those population databases include individuals with late onset disorders like diabetes mellitus. The c.1672C>T variant is located in exon 8 of this 8-exon gene and predicted to replace an evolutionarily conserved arginine aminoacid with cysteine at position 558 (p.(Arg558Cys)) in the cytoplasmic linker region connecting transmembrane domains VI and VII of the encoded protein [see Figure 1 in PMID:20301750]. In silico predictions are moderately in favor of damaging effect for p.(Arg558Cys) [CADD v1.6 = 25.5,REVEL = 0.816]; however, there are no functional studies to support or refute these predictions. Another variant affecting the same amino acid residue(c.1673G>A:p.(Arg558His)) has also been reported in the literature [PMID: 12754709, 21446023, 24890733, 31567480] and ClinVar [ClinVar ID: 427051] in individuals with late-onset Wolfram syndrome. Based on available evidence the c.1672C>T p.(Arg558Cys) variant identified in WFS1 is classified as Pathogenic for autosomal recessive late-onset Wolfram syndrome.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000255189	SCV004563959	likely pathogenic	not provided	2023-10-16	criteria provided, single submitter	clinical testing	The WFS1 c.1672C>T; p.Arg558Cys variant (rs199946797) is reported in the literature in the compound heterozygous or homozygous state in several individuals affected with Wolfram syndrome, although this variant is often associated with a mild or atypical, later-onset form of disease (Astuti 2017, Bansal 2018, Cano 2007, Chaussenot 2015, Grenier 2016, Pan 2019, Ustaoglu 2020, Wilf-Yarkoni 2021, Zhang 2022). This variant is found in the general population with an overall allele frequency of 0.063% (177/281960 alleles), and may be a founder variant in the Ashkenazi Jewish population with an allele frequency of 1.34% (139/10366 alleles, including a single homozygote) in the Genome Aggregation Database. This variant is also reported in ClinVar (Variation ID: 198835), and computational analyses predict that this variant is deleterious (REVEL: 0.816). Additionally, another variant at this codon (c.1673G>A; p.Arg558His) has been reported in individuals with Wolfram syndrome and is considered pathogenic (Grenier 2016, Zhang 2022). Based on available information, this variant is considered to be likely pathogenic. References: Astuti D et al. Monogenic diabetes syndromes: Locus-specific databases for Alström, Wolfram, and Thiamine-responsive megaloblastic anemia. Hum Mutat. 2017 Jul;38(7):764-777. PMID: 28432734. Bansal V et al. Identification of a missense variant in the WFS1 gene that causes a mild form of Wolfram syndrome and is associated with risk for type 2 diabetes in Ashkenazi Jewish individuals. Diabetologia. 2018 Oct;61(10):2180-2188. PMID: 30014265. Cano et al. Identification of novel mutations in WFS1 and genotype-phenotype correlation in Wolfram syndrome. Am J Med Genet A. 2007 Jul 15;143A(14):1605-12. Chaussenot et al. Mutation update and uncommon phenotypes in a French cohort of 96 patients with WFS1-related disorders. Clin Genet. 2015 May;87(5):430-9. Grenier J et al. WFS1 in Optic Neuropathies: Mutation Findings in Nonsyndromic Optic Atrophy and Assessment of Clinical Severity. Ophthalmology. 2016 Sep;123(9):1989-98. PMID: 27395765. Pan YD et al. Compound heterozygous mutations in WFS1 cause atypical Wolfram syndrome. Chin Med J (Engl). 2019 Oct 20;132(20):2508-2509. PMID: 31567480. Ustaoglu M et al. Ophthalmic, systemic, and genetic characteristics of patients with Wolfram syndrome. Eur J Ophthalmol. 2020 Sep;30(5):1099-1105. PMID: 30957632. Wilf-Yarkoni A et al. Mild Phenotype of Wolfram Syndrome Associated With a Common Pathogenic Variant Is Predicted by a Structural Model of Wolframin. Neurol Genet. 2021 Mar 19;7(2):e578. PMID: 33763535. Zhang X et al. Comprehensive Genetic Analysis Unraveled the Missing Heritability in a Chinese Cohort With Wolfram Syndrome 1: Clinical and Genetic Findings. Invest Ophthalmol Vis Sci. 2022 Sep 1;63(10):9. PMID: 36098976.
Constantin Polychronakos Laboratory, The Research Institute of the McGill University Health Centre	RCV001175325	SCV001250642	pathogenic	Diabetes mellitus		no assertion criteria provided	research	PS1 PM2 PP3 PP4
PreventionGenetics, part of Exact Sciences	RCV004537507	SCV004114884	likely pathogenic	WFS1-related disorder	2023-11-25	no assertion criteria provided	clinical testing	The WFS1 c.1672C>T variant is predicted to result in the amino acid substitution p.Arg558Cys. This variant was reported in the compound heterozygous and homozygous states in individuals with features of Wolfram syndrome (Cano et al. 2007. PubMed ID: 17568405; Lieber et al 2012. PubMed ID: 22226368; Ustaoglu et al 2019. PubMed ID: 30957632). This variant has also been reported, with uncertain significance, in an individual with sporadic ataxia (Fogel et al 2014. PubMed ID: 25133958) and in an individual with schizophrenia (Torres et al 2001. PubMed ID: 11244483). This variant is reported in 1.3% of alleles in individuals of Ashkenazi Jewish descent in gnomAD, including one homozygote. This variant in the homozygous state was found to significantly increase risk for type 1 diabetes in a cohort of Ashkenazi Jewish patients, although age at diabetes diagnosis was later than usual and other features of Wolfram syndrome were absent in most patients, suggesting this variant has a mild effect compared to other Wolfram syndrome causative variants (Bansal et al. 2018. PubMed ID: 30014265). This variant is interpreted as likely pathogenic.
Undiagnosed Diseases Network, NIH	RCV001706152	SCV004812022	pathogenic	Wolfram syndrome 1	2023-12-19	no assertion criteria provided	clinical testing