Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV002608443 | SCV002956204 | pathogenic | not provided | 2023-11-07 | criteria provided, single submitter | clinical testing | This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 193 of the SCO2 protein (p.Gly193Ser). This variant is present in population databases (rs759452074, gnomAD 0.03%). This missense change has been observed in individuals with clinical features of cardioencephalomyopathy (PMID: 19353847, 29193756, 32600061). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 1913825). 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 SCO2 protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV003235733 | SCV003933796 | pathogenic | Cardioencephalomyopathy, fatal infantile, due to cytochrome c oxidase deficiency 1 | 2023-05-15 | criteria provided, single submitter | clinical testing | Variant summary: SCO2 c.577G>A (p.Gly193Ser) results in a non-conservative amino acid change located in the Thioredoxin domain (IPR013766) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.2e-05 in 251350 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.577G>A has been reported in the literature in both compound heterozygous and homozygous individuals affected with Mitochondrial complex IV deficiency (e.g., Mobley_2009, Ogawa_2017, Hirono_2020) as well as an individual with mitochondrial complex IV deficiency presenting with adult-onset, slowly-progressive cerebellar ataxia, sensoral nueronopathy, deafness, pigmentary retinopathy, and cataract (e.g., Rucheton_2021). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, finding that the variant results in mitochondrial ultrastructural abnormalities and a severely attenuated response to inotropic interventions in induced pluripotent stem cell-derived cardiomyocytes from a homozygous patient (e.g., Hallas_2018). The following publications have been ascertained in the context of this evaluation (PMID: 29193756, 32600061, 19353847, 28429146, 34746378). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. |
| Baylor Genetics | RCV003235733 | SCV004202355 | pathogenic | Cardioencephalomyopathy, fatal infantile, due to cytochrome c oxidase deficiency 1 | 2024-03-01 | criteria provided, single submitter | clinical testing | |
| Mayo Clinic Laboratories, |
RCV002608443 | SCV004226174 | likely pathogenic | not provided | 2023-06-15 | criteria provided, single submitter | clinical testing | PP3, PP4, PM2, PM3 |
| Fulgent Genetics, |
RCV005032330 | SCV005663920 | pathogenic | Cardioencephalomyopathy, fatal infantile, due to cytochrome c oxidase deficiency 1; Myopia 6 | 2024-03-21 | criteria provided, single submitter | clinical testing |