ClinVar Genomic variation as it relates to human health
NM_198076.6(COX20):c.157+3G>C
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.
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_198076.6(COX20):c.157+3G>C
Variation ID: 380082 Accession: VCV000380082.19
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 1q44 1: 244842061 (GRCh38) [ NCBI UCSC ] 1: 245005363 (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 Mar 8, 2017 Feb 20, 2024 Jan 26, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_198076.6:c.157+3G>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
intron variant NM_001312871.1:c.157+3G>C intron variant NM_001312872.1:c.193+3G>C intron variant NM_001312873.1:c.23-134G>C intron variant NM_001312874.1:c.157+3G>C intron variant NC_000001.11:g.244842061G>C NC_000001.10:g.245005363G>C NG_042825.1:g.11756G>C - Protein change
- Other names
- IVS2, G-C, +3
- Canonical SPDI
- NC_000001.11:244842060:G:C
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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
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The frequency of the allele represented by this VCV record.
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00038
Exome Aggregation Consortium (ExAC) 0.00057
Trans-Omics for Precision Medicine (TOPMed) 0.00065
The Genome Aggregation Database (gnomAD) 0.00066
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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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. |
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COX20 | - | - |
GRCh38 GRCh37 |
78 | 214 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Likely pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Jan 26, 2024 | RCV000441332.11 | |
no classifications from unflagged records (1) |
no classifications from unflagged records
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Sep 13, 2023 | RCV000763846.3 | |
Pathogenic/Likely pathogenic (5) |
criteria provided, multiple submitters, no conflicts
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May 9, 2023 | RCV001526453.7 |
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
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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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Pathogenic
(Dec 18, 2020)
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criteria provided, single submitter
Method: clinical testing
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Mitochondrial complex 4 deficiency, nuclear type 11
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
maternal
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Undiagnosed Diseases Network, NIH
Study: Undiagnosed Diseases Network (NIH), UDN
Accession: SCV001736866.1 First in ClinVar: Jun 19, 2021 Last updated: Jun 19, 2021 |
Number of individuals with the variant: 1
Clinical Features:
Esotropia (present) , Cerebellar ataxia (present) , Dysarthria (present) , Cerebral atrophy (present) , Sensory axonal neuropathy (present)
Age: 30-39 years
Sex: female
Ethnicity/Population group: Caucasians
Tissue: blood
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Likely pathogenic
(Jun 30, 2021)
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criteria provided, single submitter
Method: clinical testing
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Mitochondrial complex 4 deficiency, nuclear type 11
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV001752704.1
First in ClinVar: Jul 18, 2021 Last updated: Jul 18, 2021 |
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Likely pathogenic
(Jun 17, 2022)
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criteria provided, single submitter
Method: clinical testing
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Mitochondrial complex 4 deficiency, nuclear type 11
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV003835234.1
First in ClinVar: Mar 11, 2023 Last updated: Mar 11, 2023 |
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Likely pathogenic
(May 05, 2023)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000517782.8
First in ClinVar: Mar 08, 2017 Last updated: May 13, 2023 |
Comment:
Published mRNA and protein analysis in fibroblasts from an individual with this variant demonstrated an absence of full-length mRNA and COX20 protein (Otero et al., … (more)
Published mRNA and protein analysis in fibroblasts from an individual with this variant demonstrated an absence of full-length mRNA and COX20 protein (Otero et al., 2019); In silico analysis supports a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 32999401, 32606554, 32827528, 30656193) (less)
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Pathogenic
(May 09, 2023)
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criteria provided, single submitter
Method: clinical testing
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Mitochondrial complex 4 deficiency, nuclear type 11
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV003934262.1
First in ClinVar: Jun 24, 2023 Last updated: Jun 24, 2023 |
Comment:
Variant summary: COX20 c.157+3G>C alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly … (more)
Variant summary: COX20 c.157+3G>C alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Three predict the variant abolishes a canonical 5' splicing donor site. This impact on normal splicing was confirmed experimentally using fibroblasts from a compound heterozygous patient: only mRNA transcripts missing exon 2 could be detected, and full length COX20 mRNA transcripts were completely absent (Otero_2019). Furthermore, no protein products could be detected from these same patient fibroblasts, indicating a complete loss of protein product (Otero_2019). The variant allele was found at a frequency of 0.00057 in 249980 control chromosomes (gnomAD). c.157+3G>C has been reported in the literature as a biallelic genotype in multiple individuals affected with Mitochondrial Complex 4 Deficiency, Nuclear Type 11 (e.g. Otero_2019, Chakravorty_2020, Naess_2021). These data indicate that the variant is very likely to be associated with disease.The following publications have been ascertained in the context of this evaluation (PMID: 32999401, 32827528, 30656193). Seven ClinVar submitters have assessed the variant since 2014: one classified the variant as uncertain significance, four as likely pathogenic, and two as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Likely pathogenic
(Jan 26, 2024)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV002255160.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 20, 2024 |
Comment:
This sequence change falls in intron 2 of the COX20 gene. It does not directly change the encoded amino acid sequence of the COX20 protein. … (more)
This sequence change falls in intron 2 of the COX20 gene. It does not directly change the encoded amino acid sequence of the COX20 protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs367956888, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This variant has been observed in individuals with clinical features of mitochondrial complex IV deficiency (PMID: 30656193, 32827528, 32999401). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 380082). Studies have shown that this variant alters COX20 gene expression (PMID: 30656193). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. (less)
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Uncertain significance
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001740199.3 First in ClinVar: Jul 07, 2021 Last updated: Sep 08, 2021 |
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Uncertain significance
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001973233.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021 |
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Pathogenic
(Feb 04, 2022)
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no assertion criteria provided
Method: literature only
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MITOCHONDRIAL COMPLEX IV DEFICIENCY, NUCLEAR TYPE 11
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV002073673.1
First in ClinVar: Feb 13, 2022 Last updated: Feb 13, 2022 |
Comment on evidence:
For discussion of the c.157+3G-C splice site mutation in the COX20 gene, resulting in skipping of exon 2, that was found in compound heterozygous state … (more)
For discussion of the c.157+3G-C splice site mutation in the COX20 gene, resulting in skipping of exon 2, that was found in compound heterozygous state in 4 patients from 3 unrelated families with mitochondrial complex IV deficiency nuclear type 11 (MC4D11; 619054) by Otero et al. (2019), see 614698.0002. (less)
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Uncertain significance
(Oct 31, 2018)
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Flagged submission
flagged submission
Method: clinical testing
Reason: New submission from submitter that appears to have been intended to update this older submission
Source: ClinGen
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Mitochondrial complex IV deficiency, nuclear type 1
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV000894775.1
First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019 |
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Flagged submissions do not contribute to the aggregate classification or review status for the variant. Learn more |
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. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Clinical Presentation, Genetic Etiology, and Coenzyme Q10 Levels in 55 Children with Combined Enzyme Deficiencies of the Mitochondrial Respiratory Chain. | Naess K | The Journal of pediatrics | 2021 | PMID: 32827528 |
Expanding the genotype-phenotype correlation of childhood sensory polyneuropathy of genetic origin. | Chakravorty S | Scientific reports | 2020 | PMID: 32999401 |
Novel pathogenic COX20 variants causing dysarthria, ataxia, and sensory neuropathy. | Otero MG | Annals of clinical and translational neurology | 2018 | PMID: 30656193 |
Aberrant 5' splice sites in human disease genes: mutation pattern, nucleotide structure and comparison of computational tools that predict their utilization. | Buratti E | Nucleic acids research | 2007 | PMID: 17576681 |
Statistical features of human exons and their flanking regions. | Zhang MQ | Human molecular genetics | 1998 | PMID: 9536098 |
Text-mined citations for rs367956888 ...
HelpRecord last updated Apr 15, 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.