Submissions for variant NM_005138.3(SCO2):c.418G>A (p.Glu140Lys)

gnomAD frequency: 0.00011  dbSNP: rs74315511

Total submissions: 19

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000198477	SCV000252240	pathogenic	not provided	2022-04-06	criteria provided, single submitter	clinical testing	Observed in homozygous state in unrelated patients referred for genetic testing at GeneDx with hypotonia, developmental delay, feeding issues, and tremor and not observed in homozygous state in controls; Functional studies indicate that E140K may perturb the complex IV assembly process (Yang et al., 2010); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 12020273, 10749987, 34670123, 28798025, 23643385, 19879173, 25058219, 23719228, 11673586, 14994243, 16765077, 18924171, 23407777, 14970747, 15210538, 12538779, 22515166, 19837698, 16083427, 16326995, 10545952, 29351582, 27290639, 31623504, 29193756, 34426522, 34691145, 31589614, 32668698, 33098801)
Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	RCV000006035	SCV000680367	pathogenic	Cardioencephalomyopathy, fatal infantile, due to cytochrome c oxidase deficiency 1	2017-09-08	criteria provided, single submitter	clinical testing
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000626777	SCV000747480	pathogenic	Seizure; Severe global developmental delay	2017-01-01	criteria provided, single submitter	clinical testing
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000006035	SCV001369322	pathogenic	Cardioencephalomyopathy, fatal infantile, due to cytochrome c oxidase deficiency 1	2019-10-17	criteria provided, single submitter	clinical testing	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PS3,PM2,PM3,PP3.
Institute of Human Genetics, University of Leipzig Medical Center	RCV000006035	SCV001429182	pathogenic	Cardioencephalomyopathy, fatal infantile, due to cytochrome c oxidase deficiency 1	2023-01-03	criteria provided, single submitter	clinical testing	This variant was identified as homozygous._x000D_ Criteria applied: PM3_VSTR, PM1, PM2_SUP, PP3
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000198477	SCV001446799	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000006035	SCV001530277	pathogenic	Cardioencephalomyopathy, fatal infantile, due to cytochrome c oxidase deficiency 1	2024-03-29	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000198477	SCV002238714	pathogenic	not provided	2025-01-01	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 140 of the SCO2 protein (p.Glu140Lys). This variant is present in population databases (rs74315511, gnomAD 0.02%). This missense change has been observed in individual(s) with cardioencephalomyopathy (PMID: 10545952, 15210538, 16765077, 23719228). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 5681). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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.
CeGaT Center for Human Genetics Tuebingen	RCV000198477	SCV002496759	pathogenic	not provided	2023-06-01	criteria provided, single submitter	clinical testing	SCO2: PS1, PM2, PM3, PP3, PS3:Supporting
AiLife Diagnostics, AiLife Diagnostics	RCV000198477	SCV002502644	pathogenic	not provided	2022-03-24	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV005031395	SCV005663923	pathogenic	Cardioencephalomyopathy, fatal infantile, due to cytochrome c oxidase deficiency 1; Myopia 6	2024-02-16	criteria provided, single submitter	clinical testing
OMIM	RCV000006035	SCV000026217	pathogenic	Cardioencephalomyopathy, fatal infantile, due to cytochrome c oxidase deficiency 1	2013-05-02	no assertion criteria provided	literature only
OMIM	RCV000043619	SCV000071644	pathogenic	Myopia 6	2013-05-02	no assertion criteria provided	literature only
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000198477	SCV001739789	pathogenic	not provided		no assertion criteria provided	clinical testing
Practice for Gait Abnormalities, David Pomarino, Competency Network Toe Walking c/o Practice Pomarino	RCV001610286	SCV001832611	pathogenic	Tip-toe gait	2021-08-18	flagged submission	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000198477	SCV001928488	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000198477	SCV001964684	pathogenic	not provided		no assertion criteria provided	clinical testing
Solve-RD Consortium	RCV000043619	SCV005091319	likely pathogenic	Myopia 6	2022-06-01	no assertion criteria provided	provider interpretation	Variant confirmed as disease-causing by referring clinical team
PreventionGenetics, part of Exact Sciences	RCV004752685	SCV005361451	pathogenic	SCO2-related disorder	2024-09-25	no assertion criteria provided	clinical testing	The SCO2 c.418G>A variant is predicted to result in the amino acid substitution p.Glu140Lys. This variant has been frequently reported to be causative for autosomal recessive cardio-encephalomyopathy due to cytochrome c oxidase (COX) deficiency-1 (CEMCOX1) and other SCO2-related disorders (Pronicka et al. 2013. PubMed ID: 23719228; Jaksch et al. 2001. PubMed ID: 11673586; Papadopoulou et al. 1999. PubMed ID: 10545952). This variant is reported in 0.018% of alleles in individuals of European (non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic.