Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000498081 | SCV000590099 | uncertain significance | not provided | 2017-06-05 | criteria provided, single submitter | clinical testing | The R755H variant in the OPA1 gene has not been reported previously in any individual with an OPA1-related disorder as a pathogenic variant, nor as a benign variant, to our knowledge. This variant is observed in 1/10,388 alleles (0.0096%) from individuals of African background in the ExAC dataset (Lek et al., 2016). The R755H variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. However, this substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret R755H as a variant of uncertain significance. |
| Invitae | RCV000498081 | SCV002253553 | uncertain significance | not provided | 2024-01-10 | 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 755 of the OPA1 protein (p.Arg755His). This variant is present in population databases (rs762258708, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with OPA1-related conditions. ClinVar contains an entry for this variant (Variation ID: 432381). 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 OPA1 protein function with a negative predictive value of 80%. 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, |
RCV002481584 | SCV002786541 | uncertain significance | Abortive cerebellar ataxia; Glaucoma, normal tension, susceptibility to; Optic atrophy with or without deafness, ophthalmoplegia, myopathy, ataxia, and neuropathy; Autosomal dominant optic atrophy classic form; Mitochondrial DNA depletion syndrome 14 (cardioencephalomyopathic type) | 2022-01-10 | criteria provided, single submitter | clinical testing | |
| Ambry Genetics | RCV002524081 | SCV003694889 | uncertain significance | Inborn genetic diseases | 2022-06-21 | criteria provided, single submitter | clinical testing | The c.2264G>A (p.R755H) alteration is located in exon 22 (coding exon 22) of the OPA1 gene. This alteration results from a G to A substitution at nucleotide position 2264, causing the arginine (R) at amino acid position 755 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. |