The c.268C>T;p.(Arg90*) variant creates a premature translational stop signal in the SCO2 gene. It is expected to result in an absent or disrupted protein product - PVS1. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 5682; PMID: 10749987; PMID:33171185; PMID:23719228) - PS4. The variant is present at low allele frequencies population databases (rs74315512 – gnomAD 0.0001620%; ABraOM no frequency - https://abraom.ib.usp.br/) - PM2_supporting. In summary, the currently available evidence indicates that the variant is pathogenic.
ClinVar Genomic variation as it relates to human health
NM_005138.3(SCO2):c.268C>T (p.Arg90Ter)
Germline
Classification
Help
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
(6)
Help
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Pathogenic/Likely pathogenic
6
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_005138.3(SCO2):c.268C>T (p.Arg90Ter)
Variation ID: 5682 Accession: VCV000005682.9
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 22q13.33 22: 50524144 (GRCh38) [ NCBI UCSC ] 22: 50962573 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Oct 13, 2016 Jun 17, 2024 Nov 20, 2023 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_005138.3:c.268C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_005129.2:p.Arg90Ter nonsense NM_152299.4:c.*769G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
3 prime UTR NM_001169109.2:c.268C>T NP_001162580.1:p.Arg90Ter nonsense NM_001169110.1:c.268C>T NP_001162581.1:p.Arg90Ter nonsense NM_001169111.2:c.268C>T NP_001162582.1:p.Arg90Ter nonsense NM_001185011.2:c.*769G>A 3 prime UTR NC_000022.11:g.50524144G>A NC_000022.10:g.50962573G>A NG_011860.1:g.10942C>T NG_016235.1:g.7296C>T NG_021419.1:g.20929G>A LRG_727:g.10942C>T - Protein change
- R90*
- Other names
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p.Arg90*
- Canonical SPDI
- NC_000022.11:50524143:G:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
- -
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
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Trans-Omics for Precision Medicine (TOPMed) 0.00000
The Genome Aggregation Database (gnomAD), exomes 0.00002
Exome Aggregation Consortium (ExAC) 0.00003
- Links
Genes
| Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
|---|---|---|---|---|---|---|
| HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
|||
| NCAPH2 | - | - |
GRCh38 GRCh37 |
53 | 573 | |
| SCO2 | - | - |
GRCh38 GRCh37 |
4 | 884 | |
Conditions - Germline
| Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
|---|---|---|---|---|
| Pathogenic/Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Nov 20, 2023 | RCV000006036.8 | |
| Pathogenic (1) |
criteria provided, single submitter
|
May 13, 2023 | RCV001851688.4 | |
| Pathogenic/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Nov 3, 2022 | RCV001650831.3 |
Submissions - Germline
| Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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|---|---|---|---|---|---|
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Pathogenic
(Nov 03, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Myopia 6
Affected status: unknown
Allele origin:
germline
|
DASA
Accession: SCV002588789.1
First in ClinVar: Nov 05, 2022 Last updated: Nov 05, 2022 |
Comment:
The c.268C>T;p.(Arg90*) variant creates a premature translational stop signal in the SCO2 gene. It is expected to result in an absent or disrupted protein product … (more)
The c.268C>T;p.(Arg90*) variant creates a premature translational stop signal in the SCO2 gene. It is expected to result in an absent or disrupted protein product - PVS1. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 5682; PMID: 10749987; PMID:33171185; PMID:23719228) - PS4. The variant is present at low allele frequencies population databases (rs74315512 – gnomAD 0.0001620%; ABraOM no frequency - https://abraom.ib.usp.br/) - PM2_supporting. In summary, the currently available evidence indicates that the variant is pathogenic. (less)
Number of individuals with the variant: 1
Sex: male
Geographic origin: Brazil
|
|
|
Pathogenic
(May 13, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV002192109.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the SCO2 protein in which other variant(s) (p.Glu140Lys) have … (more)
For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the SCO2 protein in which other variant(s) (p.Glu140Lys) have been determined to be pathogenic (PMID: 10545952, 15210538, 16765077, 23719228). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 5682). This premature translational stop signal has been observed in individual(s) with autosomal recessive cardioencephalomyopathy (PMID: 10749987). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs74315512, gnomAD 0.003%). This sequence change creates a premature translational stop signal (p.Arg90*) in the SCO2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 177 amino acid(s) of the SCO2 protein. (less)
|
|
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Likely pathogenic
(Mar 25, 2021)
|
criteria provided, single submitter
Method: research
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Myopia 6
Affected status: yes
Allele origin:
maternal
|
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology
Study: AGHI WGS
Accession: SCV001870347.1 First in ClinVar: Sep 19, 2021 Last updated: Sep 19, 2021 |
Comment:
ACMG codes:PVS1, PM2
Number of individuals with the variant: 1
Clinical Features:
Thin upper lip vermilion (present) , Microcephaly (present) , Long philtrum (present) , Bulbous nose (present) , Intellectual disability (present) , Short stature (present) , … (more)
Thin upper lip vermilion (present) , Microcephaly (present) , Long philtrum (present) , Bulbous nose (present) , Intellectual disability (present) , Short stature (present) , Horizontal eyebrow (present) (less)
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Likely pathogenic
(Mar 26, 2021)
|
criteria provided, single submitter
Method: clinical testing
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Cardioencephalomyopathy, fatal infantile, due to cytochrome c oxidase deficiency 1
Affected status: yes
Allele origin:
germline
|
Clinical Genomics Laboratory, Stanford Medicine
Accession: SCV004240760.1
First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024 |
Comment:
• The p.Arg90* variant in the SCO2 gene has previously been reported in trans with a pathogenic variant (p.E140K) in two siblings affected with cytochrome … (more)
• The p.Arg90* variant in the SCO2 gene has previously been reported in trans with a pathogenic variant (p.E140K) in two siblings affected with cytochrome c oxidase deficiency, consistent with autosomal recessive inheritance (Jaksch et al., 2000). • This variant has been identified in 3/111,340 (0.0027%) European (non-Finnish) chromosomes by the Genome Aggregation Database (http://gnomad.broadinstitute.org/). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. • The p.Arg90* variant leads to a premature stop codon in exon 1 of 1 coding exons, removing 227 amino acids and a majority of the thioredoxim domain, resulting in a truncated protein. • These data were assessed using the ACMG/AMP variant interpretation guidelines. In summary, there is sufficient evidence to classify the p.Arg90* variant as likely pathogenic for cytochrome c oxidase deficiency syndrome in an autosomal recessive manner based on the information above. [ACMG evidence codes used: PVS1_Strong; PM2; PM3] (less)
|
|
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Pathogenic
(Nov 20, 2023)
|
criteria provided, single submitter
Method: clinical testing
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Cardioencephalomyopathy, fatal infantile, due to cytochrome c oxidase deficiency 1
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV005055575.1
First in ClinVar: Jun 17, 2024 Last updated: Jun 17, 2024 |
|
|
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Pathogenic
(Mar 22, 2000)
|
no assertion criteria provided
Method: literature only
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MITOCHONDRIAL COMPLEX IV DEFICIENCY, NUCLEAR TYPE 2
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000026218.3
First in ClinVar: Apr 04, 2013 Last updated: Aug 02, 2020 |
Comment on evidence:
In a pair of sibs (family B) with mitochondrial complex IV deficiency nuclear type 2 (MC4DN2; 604377) manifesting as fatal infantile cardioencephalomyopathy, Jaksch et al. … (more)
In a pair of sibs (family B) with mitochondrial complex IV deficiency nuclear type 2 (MC4DN2; 604377) manifesting as fatal infantile cardioencephalomyopathy, Jaksch et al. (2000) detected a c.1391C-T transition in the SCO2 gene, resulting in an amino acid change of arg90 to ter (R90X). The sibs also were heterozygous for the glu140 to lys (604272.0002) mutation, present in the father. The mother carried the R90X mutation. (less)
|
Comment:
Comment:
For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the SCO2 protein in which other variant(s) (p.Glu140Lys) have been determined to be pathogenic (PMID: 10545952, 15210538, 16765077, 23719228). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 5682). This premature translational stop signal has been observed in individual(s) with autosomal recessive cardioencephalomyopathy (PMID: 10749987). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs74315512, gnomAD 0.003%). This sequence change creates a premature translational stop signal (p.Arg90*) in the SCO2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 177 amino acid(s) of the SCO2 protein.
Comment:
ACMG codes:PVS1, PM2
Comment:
• The p.Arg90* variant in the SCO2 gene has previously been reported in trans with a pathogenic variant (p.E140K) in two siblings affected with cytochrome c oxidase deficiency, consistent with autosomal recessive inheritance (Jaksch et al., 2000). • This variant has been identified in 3/111,340 (0.0027%) European (non-Finnish) chromosomes by the Genome Aggregation Database (http://gnomad.broadinstitute.org/). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. • The p.Arg90* variant leads to a premature stop codon in exon 1 of 1 coding exons, removing 227 amino acids and a majority of the thioredoxim domain, resulting in a truncated protein. • These data were assessed using the ACMG/AMP variant interpretation guidelines. In summary, there is sufficient evidence to classify the p.Arg90* variant as likely pathogenic for cytochrome c oxidase deficiency syndrome in an autosomal recessive manner based on the information above. [ACMG evidence codes used: PVS1_Strong; PM2; PM3]
Germline Functional Evidence
| There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Comment:
The c.268C>T;p.(Arg90*) variant creates a premature translational stop signal in the SCO2 gene. It is expected to result in an absent or disrupted protein product - PVS1. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 5682; PMID: 10749987; PMID:33171185; PMID:23719228) - PS4. The variant is present at low allele frequencies population databases (rs74315512 – gnomAD 0.0001620%; ABraOM no frequency - https://abraom.ib.usp.br/) - PM2_supporting. In summary, the currently available evidence indicates that the variant is pathogenic.
Comment:
For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the SCO2 protein in which other variant(s) (p.Glu140Lys) have been determined to be pathogenic (PMID: 10545952, 15210538, 16765077, 23719228). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 5682). This premature translational stop signal has been observed in individual(s) with autosomal recessive cardioencephalomyopathy (PMID: 10749987). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs74315512, gnomAD 0.003%). This sequence change creates a premature translational stop signal (p.Arg90*) in the SCO2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 177 amino acid(s) of the SCO2 protein.
Comment:
ACMG codes:PVS1, PM2
Comment:
• The p.Arg90* variant in the SCO2 gene has previously been reported in trans with a pathogenic variant (p.E140K) in two siblings affected with cytochrome c oxidase deficiency, consistent with autosomal recessive inheritance (Jaksch et al., 2000). • This variant has been identified in 3/111,340 (0.0027%) European (non-Finnish) chromosomes by the Genome Aggregation Database (http://gnomad.broadinstitute.org/). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. • The p.Arg90* variant leads to a premature stop codon in exon 1 of 1 coding exons, removing 227 amino acids and a majority of the thioredoxim domain, resulting in a truncated protein. • These data were assessed using the ACMG/AMP variant interpretation guidelines. In summary, there is sufficient evidence to classify the p.Arg90* variant as likely pathogenic for cytochrome c oxidase deficiency syndrome in an autosomal recessive manner based on the information above. [ACMG evidence codes used: PVS1_Strong; PM2; PM3]
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Cytochrome c oxidase deficiency. | Brischigliaro M | Biochimica et biophysica acta. Bioenergetics | 2021 | PMID: 33171185 |
| The natural history of SCO2 deficiency in 36 Polish children confirmed the genotype-phenotype correlation. | Pronicka E | Mitochondrion | 2013 | PMID: 23719228 |
| A hemizygous SCO2 mutation in an early onset rapidly progressive, fatal cardiomyopathy. | Leary SC | Molecular genetics and metabolism | 2006 | PMID: 16765077 |
| Association of mutations in SCO2, a cytochrome c oxidase assembly gene, with early fetal lethality. | Tay SK | Archives of neurology | 2004 | PMID: 15210538 |
| Mutations in SCO2 are associated with a distinct form of hypertrophic cardiomyopathy and cytochrome c oxidase deficiency. | Jaksch M | Human molecular genetics | 2000 | PMID: 10749987 |
| Fatal infantile cardioencephalomyopathy with COX deficiency and mutations in SCO2, a COX assembly gene. | Papadopoulou LC | Nature genetics | 1999 | PMID: 10545952 |
Text-mined citations for rs74315512 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Sep 29, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.