Submissions for variant NM_006005.3(WFS1):c.2603G>A (p.Arg868His)

gnomAD frequency: 0.00010  dbSNP: rs56393026

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000199675	SCV000252547	uncertain significance	not provided	2024-09-13	criteria provided, single submitter	clinical testing	Identified in patients with hearing loss or congenital cataracts in published literature; patients were also heterozygous for WFS1 p.(RP607L); it is unknown if the two variants are on the same allele (in cis) or on opposite alleles (in trans) (PMID: 36729443, 26969326, 36597107); Identified as a single heterozygous variant in patients with congenital cataracts in published literature (PMID: 32883240, 37592116, 37337769); 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: 34426522, Turkyilmaz2021[article], 36597107, 37592116, 26969326, 36729443, 36208030, 37337769, 32883240, 37719678)
Center of Genomic medicine, Geneva, University Hospital of Geneva	RCV000502304	SCV000598135	uncertain significance	Autistic behavior	2017-03-22	criteria provided, single submitter	clinical testing	This heterozygous variant in the WFS1 gene (autosomal recessive transmission), inherited from the mother, was present in a male child who also harbours a second variant in the same gene inherited by the father (compound heterozygosity).
Eurofins Ntd Llc (ga)	RCV000199675	SCV000709484	uncertain significance	not provided	2017-06-22	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001156283	SCV001317771	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	RCV001156284	SCV001317772	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). 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000199675	SCV002166124	uncertain significance	not provided	2025-01-13	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 868 of the WFS1 protein (p.Arg868His). This variant is present in population databases (rs56393026, gnomAD 0.02%). This missense change has been observed in individual(s) with clinical features of WFS1-related conditions (PMID: 26969326, 32883240, 36597107, 36729443). ClinVar contains an entry for this variant (Variation ID: 215403). 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) has been performed 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. 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.
Fulgent Genetics, Fulgent Genetics	RCV002485311	SCV002785399	likely pathogenic	Cataract 41; Wolfram syndrome 1; Autosomal dominant nonsyndromic hearing loss 6; Type 2 diabetes mellitus; Wolfram-like syndrome	2024-02-20	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002517282	SCV003680118	uncertain significance	Inborn genetic diseases	2024-07-18	criteria provided, single submitter	clinical testing	Unlikely to be causative of Wolfram-like syndrome (AD) Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
CeGaT Center for Human Genetics Tuebingen	RCV000199675	SCV004185217	uncertain significance	not provided	2023-11-01	criteria provided, single submitter	clinical testing	WFS1: PM5:Supporting, PS4:Supporting
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004782306	SCV005394636	uncertain significance	not specified	2024-09-25	criteria provided, single submitter	clinical testing	Variant summary: WFS1 c.2603G>A (p.Arg868His) results in a non-conservative amino acid change located in the Wolframin, OB-fold domain (IPR045461) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 9.2e-05 in 250092 control chromosomes, predominantly at a frequency of 0.0002 within the South Asian subpopulation in the gnomAD database. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2603G>A has been reported in the literature in individuals affected with nonsyndromic hearing loss and congenital cataract, without strong evidence for causality (Billings_2022, Fan_2020, Liu_2023, Ma_2023, Sloan-Heggen_2016). These report(s) do not provide unequivocal conclusions about association of the variant with Wolfram Syndrome 1. 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: 36208030, 32883240, 37337769, 36597107, 26969326). ClinVar contains an entry for this variant (Variation ID: 215403). Based on the evidence outlined above, the variant was classified as uncertain significance.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV004786526	SCV005398512	uncertain significance	Wolfram syndrome 1	2020-06-11	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as VUS - 3B. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. Truncating variants and some missense variants have been shown to result in a loss of function disease mechanism (OMIM). (N) 0104 - Dominant Negative is a known mechanism of disease for this gene. Missense variants have also been functionally proven to result in a dominant negative disease mechanism. There is no distinction between the location of the missense variants, and their disease mechanism. (PMID: 32219690). (N) 0108 - This gene is known to be associated with both recessive and dominant disease. Biallelic truncating variants, and missense variants have been reported for recessive disease, while some missense with a proven dominant negative effect on protein, have been shown to cause a dominant form of disease (PMID: 32219690). (N) 0200 - Variant is predicted to result in a missense amino acid change from arginine to histidine (exon 8). (N) 0251 - Variant is heterozygous. (N) 0304 - Variant is present in gnomAD v2 <0.01 for a recessive condition (26 heterozygotes, 0 homozygotes). (P) 0309 - An alternative amino acid change at the same position has been observed in gnomAD v2 (14 heterozygotes, 0 homozygotes). (N) 0502 - Missense variant with conflicting in silico predictions and/or uninformative conservation. (N) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (N) 0705 - No comparable variants have previous evidence for pathogenicity. An alternative change (p.Arg868Cys) has been reported as a VUS (LOVD). (N) 0808 - Previous reports of pathogenicity are conflicting. This variant has been reported as causative variant in a patient with hearing loss (PMID: 26969326), but also as a VUS (ClinVar, LOVD) and as likely benign (deafnessvariationdatabase). (N) 0905 - No segregation evidence has been identified for this variant. (N) 1007 - No published functional evidence has been identified for this variant. (N) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000199675	SCV001741173	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000199675	SCV001965884	uncertain significance	not provided		no assertion criteria provided	clinical testing