Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000490103 | SCV000577836 | likely pathogenic | not provided | 2015-04-14 | criteria provided, single submitter | clinical testing | The Q687H variant has not been published as a pathogenic variant, nor has it been reported as a benign polymorphism to our knowledge. The Q687H variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The Q687H 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 that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Missense variants in nearby residues (M683R, A684T/V/G, R685P/H, C690G/A, G695V, H696Y) have been reported in the Human Gene Mutation Database in association with Wolfram syndrome and sensorineural hearing loss (Stenson et al., 2014), supporting the functional importance of this region of the protein. Therefore, this variant is a strong candidate for a pathogenic variant, however the possibility that it is a benign variant cannot be excluded. |
| Labcorp Genetics |
RCV000490103 | SCV002268741 | uncertain significance | not provided | 2022-09-25 | criteria provided, single submitter | clinical testing | This sequence change replaces glutamine, which is neutral and polar, with histidine, which is basic and polar, at codon 687 of the WFS1 protein (p.Gln687His). This variant is present in population databases (rs760938537, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with WFS1-related conditions. ClinVar contains an entry for this variant (Variation ID: 427196). 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 expected to disrupt 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, |
RCV005034030 | SCV005667531 | uncertain significance | Cataract 41; Wolfram syndrome 1; Autosomal dominant nonsyndromic hearing loss 6; Type 2 diabetes mellitus; Wolfram-like syndrome | 2024-04-24 | criteria provided, single submitter | clinical testing |