Submissions for variant NM_006005.3(WFS1):c.2576G>A (p.Arg859Gln)

gnomAD frequency: 0.00002  dbSNP: rs121912618

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000004787	SCV000450699	uncertain significance	Autosomal dominant nonsyndromic hearing loss 6	2017-04-28	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	RCV000275899	SCV000450700	uncertain significance	WFS1-Related Spectrum Disorders	2023-08-08	criteria provided, single submitter	clinical testing	The WFS1 c.2576G>A (p.Arg859Gln) missense variant has been reported in six individuals from one family with phenotypes which overlap with WFS1 spectrum disorder (PMID: 18688868). A different amino acid substitution at the same codon (p.Arg859Pro) has been reported in multiple individuals with features of WFS1 spectrum disorder (PMID:15912360; 36098976). Multiple lines of computational evidence suggest the variant impacts the gene or gene product. Based on the available evidence, the c.2576G>A (p.Arg859Gln) variant is classified as a variant of uncertain significance for WFS1 spectrum disorder.
GeneDx	RCV000480362	SCV000568516	uncertain significance	not provided	2017-03-23	criteria provided, single submitter	clinical testing	The R859Q variant was reported to segregate with autosomal dominant sensorineural hearing loss in six affected individuals from a single family; however, an additional affected family member did not harbor R859Q (Hildebrand et al. 2008). The R859Q variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R859Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position where amino acids with similar properties to Arginine are tolerated across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. A missense variant at the same position (R859P) showed completed segregation with autosomal dominant sensorineural hearing loss in a very large family with 25 affected individuals over 5 generations (Gürtler et al. 2005). In summary, based on the currently available information, it is unclear whether the R859Q variant is a pathogenic variant or a rare benign variant.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000480362	SCV002290749	uncertain significance	not provided	2023-09-25	criteria provided, single submitter	clinical testing	This variant disrupts the p.Arg859 amino acid residue in WFS1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15912360). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. ClinVar contains an entry for this variant (Variation ID: 4529). This missense change has been observed in individual(s) with autosomal dominant nonsyndromic deafness (PMID: 18688868). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs121912618, gnomAD 0.004%). This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 859 of the WFS1 protein (p.Arg859Gln). 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	RCV002490313	SCV002783457	uncertain significance	Cataract 41; Wolfram syndrome 1; Autosomal dominant nonsyndromic hearing loss 6; Type 2 diabetes mellitus; Wolfram-like syndrome	2022-05-10	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004532289	SCV004117613	uncertain significance	WFS1-related disorder	2023-08-03	criteria provided, single submitter	clinical testing	The WFS1 c.2576G>A variant is predicted to result in the amino acid substitution p.Arg859Gln. This variant showed partial segregation with sensorineural hearing loss in a large pedigree (Hildebrand et al. 2008. PubMed ID: 18688868). This variant is reported in 0.0033% of alleles in individuals of South Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/4-6304098-G-A). In ClinVar this alteration is reported as a variant of uncertain significance by multiple clinical labs (https://www.ncbi.nlm.nih.gov/clinvar/variation/4529/). An alternate variant at the same amino acid position has also been reported to segregate completely with sensorineural hearing loss in a large family (p.Arg859Pro; Gurtler et al. 2005. PubMed ID: 15912360). Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
OMIM	RCV000004787	SCV000024963	pathogenic	Autosomal dominant nonsyndromic hearing loss 6	2008-09-01	no assertion criteria provided	literature only