NM_005138.3(SCO2):c.418G>A (p.Glu140Lys) AND not provided

Germline classification:: Pathogenic (8 submissions)
Last evaluated:: Jan 29, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000198477.25

Allele description [Variation Report for NM_005138.3(SCO2):c.418G>A (p.Glu140Lys)]

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

Genes:

NCAPH2:non-SMC condensin II complex subunit H2 [Gene - OMIM - HGNC]
SCO2:synthesis of cytochrome C oxidase 2 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

22q13.33

Genomic location:

Preferred name:

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

Other names:

SCO2, GLU140LYS (rs74315511)

HGVS:

NC_000022.11:g.50523994C>T
NG_011860.1:g.11092G>A
NG_016235.1:g.7446G>A
NG_021419.1:g.20779C>T
NM_001169109.2:c.418G>A
NM_001169110.1:c.418G>A
NM_001169111.2:c.418G>A
NM_001185011.2:c.*619C>T
NM_005138.3:c.418G>AMANE SELECT
NM_152299.4:c.*619C>TMANE SELECT
NP_001162580.1:p.Glu140Lys
NP_001162580.1:p.Glu140Lys
NP_001162581.1:p.Glu140Lys
NP_001162582.1:p.Glu140Lys
NP_001162582.1:p.Glu140Lys
NP_005129.2:p.Glu140Lys
NP_005129.2:p.Glu140Lys
LRG_727:g.11092G>A
NC_000022.10:g.50962423C>T
NM_001169109.1:c.418G>A
NM_001169111.1:c.418G>A
NM_001169111.1:c.418G>A
NM_005138.2:c.418G>A
O43819:p.Glu140Lys
p.E140K

Protein change:

E140K; GLU140LYS

Links:

UniProtKB: O43819#VAR_008874; OMIM: 604272.0002; dbSNP: rs74315511

NCBI 1000 Genomes Browser:

rs74315511

Molecular consequence:

NM_001185011.2:c.*619C>T - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
NM_152299.4:c.*619C>T - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
NM_001169109.2:c.418G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001169110.1:c.418G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001169111.2:c.418G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_005138.3:c.418G>A - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000252240	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Apr 6, 2022)	germline	clinical testing	Citation Link,
SCV001446799	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Oct 23, 2020)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001739789	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen - VKGL Data-share Consensus	no assertion criteria provided	Pathogenic	germline	clinical testing
SCV001928488	Genome Diagnostics Laboratory, University Medical Center Utrecht - VKGL Data-share Consensus See additional submitters Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	no assertion criteria provided	Pathogenic	germline	clinical testing
SCV001964684	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center - VKGL Data-share Consensus See additional submitters Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	no assertion criteria provided	Pathogenic	germline	clinical testing
SCV002238714	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 29, 2024)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 10545952, 15210538, 16765077, 23719228, 28492532
SCV002496759	CeGaT Center for Human Genetics Tuebingen	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)	Pathogenic (Jun 1, 2023)	germline	clinical testing	Citation Link,
SCV002502644	AiLife Diagnostics, AiLife Diagnostics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 24, 2022)	germline	clinical testing	PubMed (23) [See all records that cite these PMIDs] 10545952, 31589614, 23407777, 29193756, 11673586, 34426522, 16765077, 28798025, 27290639, 23719228, 19879173, 34691145, 29351582, 12020273, 32668698, 31623504, 14994243, 15210538, 25058219, 23643385, 18924171, 33098801, 25741868

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	yes	7	not provided	not provided	1	not provided	clinical testing

Citations

PubMed

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240-242.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Fatal infantile cardioencephalomyopathy with COX deficiency and mutations in SCO2, a COX assembly gene.

Papadopoulou LC, Sue CM, Davidson MM, Tanji K, Nishino I, Sadlock JE, Krishna S, Walker W, Selby J, Glerum DM, Coster RV, Lyon G, Scalais E, Lebel R, Kaplan P, Shanske S, De Vivo DC, Bonilla E, Hirano M, DiMauro S, Schon EA.

Nat Genet. 1999 Nov;23(3):333-7.

PubMed [citation]

PMID:: 10545952

See all PubMed Citations (24)

Details of each submission

From GeneDx, SCV000252240.14

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

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)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen, SCV001446799.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	1	not provided	not provided		not provided	not provided	not provided	not provided

From Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen - VKGL Data-share Consensus, SCV001739789.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Genome Diagnostics Laboratory, University Medical Center Utrecht - VKGL Data-share Consensus, SCV001928488.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center - VKGL Data-share Consensus, SCV001964684.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Invitae, SCV002238714.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

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). 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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From CeGaT Center for Human Genetics Tuebingen, SCV002496759.10

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	6	not provided	not provided	clinical testing	not provided

Description

SCO2: PS1, PM2, PM3, PP3, PS3:Supporting

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		6	not provided	not provided	not provided

From AiLife Diagnostics, AiLife Diagnostics, SCV002502644.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (23)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		1	not provided	not provided	not provided

Last Updated: Apr 15, 2024

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