ClinVar Miner

Submissions for variant NM_006005.3(WFS1):c.2213C>A (p.Ala738Asp)

gnomAD frequency: 0.00004  dbSNP: rs756962408
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV002019239 SCV002286391 uncertain significance not provided 2024-05-27 criteria provided, single submitter clinical testing This sequence change replaces alanine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 738 of the WFS1 protein (p.Ala738Asp). This variant is present in population databases (rs756962408, gnomAD 0.01%). This missense change has been observed in individual(s) with clinical features of WFS1-related conditions (PMID: 33841295, 35469785). ClinVar contains an entry for this variant (Variation ID: 1496608). 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.
GeneDx RCV002019239 SCV002521977 uncertain significance not provided 2024-02-13 criteria provided, single submitter clinical testing Observed with a pathogenic variant in patients with optic neuropathy in published literature, but it is not known whether the variants occurred on the same (in cis) or on different (in trans) chromosomes in all cases (PMID: 33841295, 35469785); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 35452662, 33841295, 35469785)
Fulgent Genetics, Fulgent Genetics RCV005032086 SCV005667544 uncertain significance Cataract 41; Wolfram syndrome 1; Autosomal dominant nonsyndromic hearing loss 6; Type 2 diabetes mellitus; Wolfram-like syndrome 2024-03-06 criteria provided, single submitter clinical testing
PreventionGenetics, part of Exact Sciences RCV004738489 SCV005348456 uncertain significance WFS1-related disorder 2024-08-06 no assertion criteria provided clinical testing The WFS1 c.2213C>A variant is predicted to result in the amino acid substitution p.Ala738Asp. This variant was reported in compound heterozygous state with loss-of-function variant in at least one individual with Optic neuropathy (Table S2, Charif et al. 2021. PubMed ID: 33841295; Majander et al. 2022. PubMed ID: 35469785). This variant is reported in 0.011% of alleles in individuals of European (Non-Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

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