Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| ARUP Laboratories, |
RCV001000723 | SCV001157768 | uncertain significance | not specified | 2018-07-31 | criteria provided, single submitter | clinical testing | The SCO1 .881T>A; p.Met294Lys variant (rs775176412), to our knowledge, has not been reported in the medical literature or gene specific databases. However, a different variant at the same codon, p.Met294Val, has been reported in a patient with a fatal infantile encephalopathy and who was compound heterozygous for p.Met294Val and a loss of function allele in SCO1 (p.Val93Ter; Leary 2013). Functional characterization of p.Met294Val protein revealed a decrease in cytochrome c oxidase (complex IV) activity, although the authors note that the reduction in activity is modest, and that pathogenicity of missense variants may be related to residual activity (Leary 2013). The p.Met294Lys variant identified in this case is found in the general population with an allele frequency in non-Finnish Europeans of 0.002% (2/111,692 alleles) in the Genome Aggregation Database. The methionine at codon 294 is moderately conserved and computational analyses (SIFT, PolyPhen-2) predict that the substituted lysine is deleterious. However, based on the available information, the clinical significance of this variant is uncertain. |
| Invitae | RCV001869421 | SCV002144692 | uncertain significance | not provided | 2021-12-02 | criteria provided, single submitter | clinical testing | 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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C35"). ClinVar contains an entry for this variant (Variation ID: 811095). This variant has not been reported in the literature in individuals affected with SCO1-related conditions. This variant is present in population databases (rs775176412, gnomAD 0.002%). This sequence change replaces methionine, which is neutral and non-polar, with lysine, which is basic and polar, at codon 294 of the SCO1 protein (p.Met294Lys). |
| Fulgent Genetics, |
RCV002481797 | SCV002779642 | uncertain significance | Mitochondrial complex 4 deficiency, nuclear type 4 | 2022-04-26 | criteria provided, single submitter | clinical testing |