Submissions for variant NM_006005.3(WFS1):c.2149G>A (p.Glu717Lys)

gnomAD frequency: 0.00004  dbSNP: rs71532863

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000518926	SCV000617491	likely pathogenic	not provided	2024-02-09	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 12955714, 21143470, 34746052, 36208030, 37510321)
Fulgent Genetics, Fulgent Genetics	RCV002490902	SCV002780099	likely pathogenic	Cataract 41; Wolfram syndrome 1; Autosomal dominant nonsyndromic hearing loss 6; Type 2 diabetes mellitus; Wolfram-like syndrome	2024-04-03	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000518926	SCV005777017	uncertain significance	not provided	2024-12-10	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 717 of the WFS1 protein (p.Glu717Lys). This variant is present in population databases (rs71532863, gnomAD 0.01%). This missense change has been observed in individual(s) with autosomal recessive Wolfram syndrome and/or clinical features of Wolfram syndrome (PMID: 11244483, 12955714, 21143470, 37510321). ClinVar contains an entry for this variant (Variation ID: 449390). 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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000518926	SCV005876810	likely pathogenic	not provided	2024-06-21	criteria provided, single submitter	clinical testing	The WFS1 c.2149G>A; p.Glu717Lys variant (rs71532863, ClinVar Variation ID: 449390) is reported in the literature in individuals affected with Wolfram syndrome and optic atrophy who had another pathogenic variant detected, although phase of variants was not provided(Alimadadi 2011, Areblom 2023, Cryns 2003). Of these individuals, four siblings were affected and had the same genotype (Alimadadi 2011). At least one heterozygous individual affected with major depression has been reported (Munshani 2021). This variant is found in the general population with an overall allele frequency of 0.002% (6/249022 alleles) in the Genome Aggregation Database (v2.1.1). Computational analyses predict that this variant is deleterious (REVEL: 0.817). Based on available information, this variant is considered to be likely pathogenic. References: Alimadadi A et al. Novel mutations of wolframin: a report with a look at the protein structure. Clin Genet. 2011 Jan;79(1):96-9. PMID: 21143470. Cryns K et al. Mutational spectrum of the WFS1 gene in Wolfram syndrome, nonsyndromic hearing impairment, diabetes mellitus, and psychiatric disease. Hum Mutat. 2003 Oct;22(4):275-87. PMID: 12955714. Areblom M et al. A Description of the Yield of Genetic Reinvestigation in Patients with Inherited Retinal Dystrophies and Previous Inconclusive Genetic Testing. Genes (Basel). 2023 Jul 8;14(7):1413. PMID: 37510321. Munshani S et al. The Impact of Mutations in Wolframin on Psychiatric Disorders. Front Pediatr. 2021 Oct 21;9:718132. PMID: 34746052.