Submissions for variant NM_006005.3(WFS1):c.124C>T (p.Arg42Ter)

gnomAD frequency: 0.00013  dbSNP: rs71530923

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000169684	SCV000221222	pathogenic	Wolfram syndrome 1	2013-11-19	criteria provided, single submitter	clinical testing	The Arg42X variant in WFS1 has not been previously identified in individuals with Wolfram syndrome, but has been identified in 0.02% (1/8540) of European American chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/; dbSNP rs71530923). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a pathogenic interpretation. This nonsense variant leads to a premature termination codon at position 42, which is predicted to lead to a truncated or absent protein. Heterozygous carries of pathogenic WFS1 variants may be at risk for developing low frequency sensorineural hearing loss and/or diabetes mellitus (Ohata 1998, Sandhu 2007, Franks 2008). In summary, this variant meets our criteria to be classified as pathogenic (http://pcpgm.partners.org/LMM).
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000514926	SCV000610547	likely pathogenic	not provided	2017-04-10	criteria provided, single submitter	clinical testing
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV001199167	SCV001370163	pathogenic	Type 2 diabetes mellitus	2016-01-01	criteria provided, single submitter	clinical testing	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PM2,PP4,PP5.
Fulgent Genetics, Fulgent Genetics	RCV001536034	SCV001752727	pathogenic	Cataract 41; Wolfram syndrome 1; Autosomal dominant nonsyndromic hearing loss 6; Type 2 diabetes mellitus; Wolfram-like syndrome	2022-02-18	criteria provided, single submitter	clinical testing
GeneDx	RCV000514926	SCV002027919	likely pathogenic	not provided	2023-08-21	criteria provided, single submitter	clinical testing	Identified in the heterozygous state in a patient with chronic progressive external ophthalmoplegia in the published literature, however, familial segregation studies could not be performed, and authors indicate that the association of this variant with the patient's phenotype is uncertain (Heighton et al., 2019); Identified in the heterozygous state in a patient with intellectual disability and autism spectrum disorder, however segregation of this variant is unknown and the patient was not reported with other features of a WFS1-related disorder (Valentino et al., 2021); Identified in a study of type 2 diabetics and controls in the literature (Fawcett et al., 2010); however, no specific information was provided; Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 34426522, 31980526, 33031055, 36208030, 34556497, 35206658, 36294752, 31521625, 34356170, 20028947)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000514926	SCV002243968	pathogenic	not provided	2024-09-22	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg42*) in the WFS1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in WFS1 are known to be pathogenic (PMID: 12955714). This variant is present in population databases (rs71530923, gnomAD 0.01%). This variant has not been observed in the literature in individuals with autosomal recessive WFS1-related conditions. This variant has been reported in individual(s) with clinical features of autosomal dominant Wolfram-like syndrome (PMID: 31521625); however, the role of the variant in this condition is currently unclear. ClinVar contains an entry for this variant (Variation ID: 189251). For these reasons, this variant has been classified as Pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV000514926	SCV002544860	pathogenic	not provided	2022-11-01	criteria provided, single submitter	clinical testing
Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic	RCV000169684	SCV002738618	likely pathogenic	Wolfram syndrome 1		criteria provided, single submitter	research	Mutations in WFS1 gene are associated with Wolfram's syndrome, an autosomal recessive condition, which cause diabetes mellitus, diabetes insipidus, deafness and optic atrophy. rs71530923 variant is also seen in patients with Diabetes Mellitus. However, the role of this particular variant is yet to be ascertained.
New York Genome Center	RCV002467643	SCV002764547	likely pathogenic	Wolfram syndrome 1; Wolfram-like syndrome	2021-03-01	criteria provided, single submitter	clinical testing	The c.124C>T, p.Arg42Ter nonsense variant identified in WFS1 has been reported individuals with Wolfram syndrome [PMID:31980526], type 2 diabetes [PMID:20028947], and chronic progressive external ophthalmoplegia [PMID:31521625]. This variant is not reported in gnomAD v3 database, indicating this is a rare allele. This nonsense variant leads to a premature termination codon at position 42, which is predicted to lead to a truncated or absent protein. Heterozygous carries of pathogenic WFS1 variants may be at risk for developing low frequency sensorineural hearing loss and/or diabetes mellitus [PMID:18040659,17603484, 9856492]. Based on the available evidence, the variant c.124C>T, p.Arg42Ter in the WFS1 gene is classified as likely pathogenic.
Ambry Genetics	RCV002515205	SCV003560140	likely pathogenic	Inborn genetic diseases	2021-09-30	criteria provided, single submitter	clinical testing	The c.124C>T (p.R42*) alteration, located in exon 2 (coding exon 1) of the WFS1 gene, consists of a C to T substitution at nucleotide position 124. This changes the amino acid from a arginine (R) to a stop codon at amino acid position 42.This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. Based on the supporting evidence, this variant is unlikely to be causative of autosomal dominant WFS1-related Wolfram syndrome and autosomal dominant WFS1-related low frequency sensorineural hearing loss; however, it would be expected to be causative of autosomal recessive WFS1-related Wolfram syndrome based on mechanism of disease. Based on data from gnomAD, the T allele has an overall frequency of 0.01% (22/225882) total alleles studied. The highest observed frequency was 0.02% (17/97912) of European (non-Finnish) alleles. Based on the available evidence, this alteration is classified as likely pathogenic.
Revvity Omics, Revvity	RCV000514926	SCV003814857	likely pathogenic	not provided	2022-02-08	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000169684	SCV003933828	pathogenic	Wolfram syndrome 1	2023-05-22	criteria provided, single submitter	clinical testing	Variant summary: WFS1 c.124C>T (p.Arg42X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 9.3e-05 in 194514 control chromosomes (i.e., 18 heterozygous carriers; gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.124C>T has been reported in the literature in at least one compound heterozygous individual affected with atypical late-onset Wolfram syndrome 1 (WFS1) without diabetes insipidus (e.g., Rigoli_2022), suggesting the variant is likely to be associated with autosomal recessive WFS1. The variant was also found to segregate with a maturity-onset diabetes of the young phenotype in at least one family (e.g., Saint-Martin_2022). Additionally, c.124C>T has been reported in heterozygous individuals affected with early-onset diabetes (e.g., Huopio_2016), chronic progressive external ophthalmoplegia (e.g., Heighton_2019), and intellectual and psychiatric disorders (e.g., Rigoli_2022, Valentino_2021), without strong evidence for causality. However, the variant was also identified in many healthy controls (e.g., Fawcett_2010, Billings_2022). These findings therefore do not allow conclusions about the association of the variant with autosomal-dominant Wolfram-like syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 30245029, 36208030, 20028947, 31521625, 31980526, 27167055, 35206658, 34556497, 34356170). Nine ClinVar submitters (evaluation after 2014) have cited the variant and all submitters classified the variant as pathogenic (n = 4) or likely pathogenic (n = 5). Based on the evidence outlined above, the variant was classified as pathogenic for autosomal recessive WFS1.
PreventionGenetics, part of Exact Sciences	RCV004528924	SCV004104060	pathogenic	WFS1-related disorder	2022-08-26	criteria provided, single submitter	clinical testing	The WFS1 c.124C>T variant is predicted to result in premature protein termination (p.Arg42*). This variant was reported in the heterozygous state in a patient with adult onset chronic progressive external ophthalmoplegia (Table S1, Heighton et al. 2019. PubMed ID: 31521625), in a study of patients with type 2 diabetes (Appendix Table 5, Fawcett et al. 2009. PubMed ID: 20028947), and in a patient with intellectual disability and autism spectrum disorder (Valentino et al. 2021. PubMed ID: 34356170). This variant is reported in 0.017% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/4-6279306-C-T). Nonsense variants in WFS1 are expected to be pathogenic. This variant is interpreted as pathogenic.
GenomeConnect, ClinGen	RCV000509458	SCV000607106	not provided	Wolfram syndrome 1; Autosomal dominant nonsyndromic hearing loss 6; Wolfram-like syndrome		no assertion provided	phenotyping only	GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.
Center for Computational Biology & Bioinformatics, University of California, San Diego	RCV004567372	SCV005049972	uncertain significance	Meniere disease	2024-06-03	no assertion criteria provided	research