Submissions for variant NM_005138.3(SCO2):c.16_17insAGCATGCAGCAGTGACTCA (p.Arg6fs)

gnomAD frequency: 0.00091  dbSNP: rs749838192

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Blueprint Genetics	RCV000208004	SCV000264220	likely pathogenic	Primary dilated cardiomyopathy	2015-12-03	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV001781624	SCV002019148	likely pathogenic	not provided	2021-06-23	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001781624	SCV002213854	pathogenic	not provided	2024-01-20	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg6Glnfs*82) in the SCO2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 261 amino acid(s) of the SCO2 protein. This variant is present in population databases (rs749838192, gnomAD 0.8%), and has an allele count higher than expected for a pathogenic variant. This premature translational stop signal has been observed in individual(s) with cardioencephalomyopathy (PMID: 20159436). This variant is also known as c.17INS19bp. ClinVar contains an entry for this variant (Variation ID: 222816). This variant disrupts a region of the SCO2 protein in which other variant(s) (p.Gln53*) have been determined to be pathogenic (PMID: 10545952, 15210538, 19879173). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
MGZ Medical Genetics Center	RCV002288836	SCV002581836	pathogenic	Cardioencephalomyopathy, fatal infantile, due to cytochrome c oxidase deficiency 1	2022-08-26	criteria provided, single submitter	clinical testing
GeneDx	RCV001781624	SCV005201462	pathogenic	not provided	2023-12-28	criteria provided, single submitter	clinical testing	Reported with a second variant, phase unknown, in an infant with respiratory failure and distal contractures (PMID: 32668698); Frameshift variant predicted to result in protein truncation in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 20159436, 32668698, 36675121)
Reproductive Health Research and Development, BGI Genomics	RCV000208004	SCV001142498	likely pathogenic	Primary dilated cardiomyopathy	2020-01-06	no assertion criteria provided	curation	NM_005138.2:c.16_17insAGCATGCAGCAGTGACTCA in the SCO2 gene has an allele frequency of 0.008 in European (Finnish) subpopulation in the gnomAD database. The p.Arg6Glnfs*82 (NM_005138.2:c.16_17insAGCATGCAGCAGTGACTCA) variant has been detected in an patient with Early-Onset Cardioencephalomyopathy, in tans with c.418G>A. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. Taken together, we interprete this variant as Pathogenic/Likely pathogenic. ACMG/AMP Criteria applied: PVS1; PM3.