Submissions for variant NM_006005.3(WFS1):c.2385G>C (p.Glu795Asp)

dbSNP: rs373310972

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000152698	SCV000202075	uncertain significance	not specified	2020-01-16	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Benign. The p.Glu795Asp variant in WFS1 has been previously reported in one individual with hearing loss, one individual with Wolfram syndrome who also had a second variant in WFS1, and one individual with hearing loss with delayed walking, strabismus and cerebral palsy who also had a second variant in WFS1 (Rohayem 2011, Kobayashi 2018, LMM data). It has also been identified in 0.03% (7/24520) of African chromosomes by gnomAD (http://gnomad.broadinstitute.org) and is reported in ClinVar (Variation ID: 166609). Glutamic acid (Glu) at position 795 is not highly conserved in mammals and evolutionary distant species, and several species (Weddell seal, bat, armadillo, 10 fish species) carry an aspartic acid (Asp), supporting that this change at this position may be tolerated, which is consistent with computational prediction tools, which suggest that that this variant may not impact the protein. In summary, while the clinical significance of the p.Glu795Asp variant is uncertain, the lack of evolutionary conservation and computational data suggest that it is more likely to be benign. ACMG/AMP Criteria applied: BP4_strong, PM2_Supporting, PM3_Supporting.
Personalized Diabetes Medicine Program, University of Maryland School of Medicine	RCV000445494	SCV000537021	uncertain significance	Monogenic diabetes	2015-07-10	criteria provided, single submitter	research	ACMG Criteria: PP5, BP5
GeneDx	RCV001574430	SCV001801249	uncertain significance	not provided	2024-01-09	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: 30245029, 28432734, 37121227, 21602428, 29529044, Yin2023[Poster])
Labcorp Genetics (formerly Invitae), Labcorp	RCV001574430	SCV002286545	uncertain significance	not provided	2024-01-02	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with aspartic acid, which is acidic and polar, at codon 795 of the WFS1 protein (p.Glu795Asp). This variant is present in population databases (rs373310972, gnomAD 0.03%). This missense change has been observed in individual(s) with WFS1-related conditions (PMID: 21602428, 29529044). ClinVar contains an entry for this variant (Variation ID: 166609). 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) performed at Invitae indicates that this missense variant is not expected to disrupt WFS1 protein function with a negative predictive value of 95%. 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.
Ambry Genetics	RCV002514939	SCV003533524	uncertain significance	Inborn genetic diseases	2022-07-24	criteria provided, single submitter	clinical testing	Unlikely to be causative of WFS1-related Wolfram syndrome (AD) or WFS1-related low frequency sensorineural hearing loss (AD) Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
New York Genome Center	RCV003335136	SCV004046576	uncertain significance	Wolfram syndrome 1; Type 2 diabetes mellitus	2022-11-13	criteria provided, single submitter	clinical testing	The c.2385G>C variant has previously been reported in an individual with sporadic hearing loss [PMID: 29529044] and in a compound heterozygous state along with p.(Asp797Val) in individual(s) from a cohort of patients with Wolfram syndrome-related diabetes [PMID:21602428]. This variant has been deposited in ClinVar [ClinVarID: 166609] as a Variant of Uncertain Significance. The c.2385G>C variant is observed in 47 alleles (0.0080% MAF with 0 homozygotes) in population databases (gnomAD v2.1.1 and v3.1.2, TOPMed Freeze 8). The c.2385G>C variant is located in exon 8 of this 8-exon gene and is predicted to replace a moderately conserved glutamic acid with aspartic acid at position 795 in the C-terminal domain of the encoded protein [PMID:29529044]. In silico predictions for p.(Glu795Asp) are inconclusive of the variant's effect [(CADD v1.6 = 21.9, REVEL = 0.522)]; however, there are no functional studies to support or refute these predictions. Based on available evidence this c.2385G>C p.(Glu795Asp) variant identified in WFS1 is classified as a Variant of Uncertain Significance.