Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000236659 | SCV000292914 | uncertain significance | not provided | 2015-06-09 | criteria provided, single submitter | clinical testing | The R481H variant has not been published as pathogenic, nor has it been reported as a benign polymorphism to our knowledge. The R481H 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 R481H variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar 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. A missense variant in a nearby residue (A485T) have been reported in the Human Gene Mutation Database in association with hereditary motor and sensory neuropathy II (Stenson et al., 2014), supporting the functional importance of this region of the protein. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic or a rare benign variant. |
| Labcorp Genetics |
RCV001857799 | SCV002149610 | uncertain significance | Charcot-Marie-Tooth disease type 2 | 2022-11-28 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 481 of the MFN2 protein (p.Arg481His). 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. 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 MFN2 protein function. ClinVar contains an entry for this variant (Variation ID: 245785). This variant has not been reported in the literature in individuals affected with MFN2-related conditions. This variant is present in population databases (rs767718891, gnomAD 0.002%). |