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

gnomAD frequency: 0.00010  dbSNP: rs56393026

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000199675	SCV000252547	uncertain significance	not provided	2022-04-11	criteria provided, single submitter	clinical testing	Reported in a patient with non-syndromic hearing loss in the presence of a second WFS1 variant, although it is unknown if the second WFS1 variant is on the opposite allele (in trans) (Sloan-Heggen et al., 2016); 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, 26969326, Turkyilmaz2021[article])
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.
Invitae	RCV000199675	SCV002166124	uncertain significance	not provided	2023-10-14	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). 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. 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	uncertain significance	Cataract 41; Wolfram syndrome 1; Autosomal dominant nonsyndromic hearing loss 6; Type 2 diabetes mellitus; Wolfram-like syndrome	2022-05-17	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002517282	SCV003680118	uncertain significance	Inborn genetic diseases	2021-06-17	criteria provided, single submitter	clinical testing	Fan, 2020; Sloan-Heggen, 2016 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
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