NM_005138.3(SCO2):c.16_17insAGCATGCAGCAGTGACTCA (p.Arg6fs) AND not provided

Germline classification:: Pathogenic/Likely pathogenic (3 submissions)
Last evaluated:: Jan 20, 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:: RCV001781624.11

Allele description [Variation Report for NM_005138.3(SCO2):c.16_17insAGCATGCAGCAGTGACTCA (p.Arg6fs)]

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

Genes:

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

Variant type:

Insertion

Cytogenetic location:

22q13.33

Genomic location:

Preferred name:

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

HGVS:

NC_000022.11:g.50524395_50524396insTGAGTCACTGCTGCATGCT
NG_011860.1:g.10690_10691insAGCATGCAGCAGTGACTCA
NG_016235.1:g.7044_7045insAGCATGCAGCAGTGACTCA
NG_021419.1:g.21180_21181insTGAGTCACTGCTGCATGCT
NM_001169109.2:c.16_17insAGCATGCAGCAGTGACTCA
NM_001169110.1:c.16_17insAGCATGCAGCAGTGACTCA
NM_001169111.2:c.16_17insAGCATGCAGCAGTGACTCA
NM_001185011.2:c.*1020_*1021insTGAGTCACTGCTGCATGCT
NM_005138.3:c.16_17insAGCATGCAGCAGTGACTCAMANE SELECT
NM_152299.4:c.*1020_*1021insTGAGTCACTGCTGCATGCTMANE SELECT
NP_001162580.1:p.Arg6fs
NP_001162580.1:p.Arg6fs
NP_001162581.1:p.Arg6fs
NP_001162582.1:p.Arg6fs
NP_005129.2:p.Arg6fs
NP_005129.2:p.Arg6fs
LRG_727:g.10690_10691insAGCATGCAGCAGTGACTCA
NC_000022.10:g.50962824_50962825insTGAGTCACTGCTGCATGCT
NM_001169109.1:c.16_17insAGCATGCAGCAGTGACTCA
NM_005138.2:c.16_17insAGCATGCAGCAGTGACTCA

Protein change:

R6fs

Links:

dbSNP: rs749838192

NCBI 1000 Genomes Browser:

rs749838192

Molecular consequence:

NM_001185011.2:c.*1020_*1021insTGAGTCACTGCTGCATGCT - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
NM_152299.4:c.*1020_*1021insTGAGTCACTGCTGCATGCT - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
NM_001169109.2:c.16_17insAGCATGCAGCAGTGACTCA - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001169110.1:c.16_17insAGCATGCAGCAGTGACTCA - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001169111.2:c.16_17insAGCATGCAGCAGTGACTCA - frameshift variant - [Sequence Ontology: SO:0001589]
NM_005138.3:c.16_17insAGCATGCAGCAGTGACTCA - frameshift variant - [Sequence Ontology: SO:0001589]

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
SCV002019148	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jun 23, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002213854	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 20, 2024)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 20159436, 10545952, 15210538, 19879173, 28492532
SCV005201462	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Dec 28, 2023)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002019148

Revvity Omics, Revvity

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Jun 23, 2021)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

SCV002213854

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jan 20, 2024)

germline

clinical testing

PubMed (5)
[See all records that cite these PMIDs]

SCV005201462

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Pathogenic
(Dec 28, 2023)

germline

clinical testing

Citation Link

Help

Summary from all submissions

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

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

A novel mutation in the SCO2 gene in a neonate with early-onset cardioencephalomyopathy.

Joost K, Rodenburg R, Piirsoo A, van den Heuvel B, Zordania R, Ounap K.

Pediatr Neurol. 2010 Mar;42(3):227-30. doi: 10.1016/j.pediatrneurol.2009.10.004.

PubMed [citation]

PMID:: 20159436

See all PubMed Citations (6)

Details of each submission

From Revvity Omics, Revvity, SCV002019148.3

#	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	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002213854.3

#	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 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.

#	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 GeneDx, SCV005201462.1

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

Description

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)

#	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

Last Updated: Sep 29, 2024

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