Variant summary: COQ9 c.730C>T (p.Arg244X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 1.2e-05 in 251792 control chromosomes. c.730C>T has been reported in the literature in at-least one individual affected with Autosomal-Recessive Neonatal-Onset Primary Coenzyme Q10 Deficiency (Coenzyme Q10 Deficiency, Primary, 5, Duncan_2009). These data indicate that the variant is likely to be associated with disease. Several publications report experimental evidence and mouse models evaluating an impact on protein function (example, Duncan_2009, Lopez_2010, Garcia-Corzo_2013, Luna-Sanchez_2015, Quinzii_2010). The most pronounced variant effect resulted in ~10% of the normal coenzyme Q10 biosynthesis rate (Duncan_2009), and the generation of a homozygous mouse model with the orthologous variant R239X showed a severe CoQ10 deficiency (Garcia-Corzo_2013, Hidalgo-Gutierrez_2019). One reputed database (GeneReviews) has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
ClinVar Genomic variation as it relates to human health
NM_020312.4(COQ9):c.730C>T (p.Arg244Ter)
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.
(5)
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
5
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_020312.4(COQ9):c.730C>T (p.Arg244Ter)
Variation ID: 431 Accession: VCV000000431.8
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 16q21 16: 57459583 (GRCh38) [ NCBI UCSC ] 16: 57493495 (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 14, 2016 Feb 14, 2024 Aug 24, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_020312.4:c.730C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_064708.1:p.Arg244Ter nonsense NC_000016.10:g.57459583C>T NC_000016.9:g.57493495C>T NG_027696.1:g.17159C>T - Protein change
- R244*
- Other names
- -
- Canonical SPDI
- NC_000016.10:57459582:C:T
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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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The Genome Aggregation Database (gnomAD), exomes 0.00001
The Genome Aggregation Database (gnomAD) 0.00002
Trans-Omics for Precision Medicine (TOPMed) 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. |
|||
| COQ9 | - | - |
GRCh38 GRCh37 |
247 | 319 | |
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 (4) |
criteria provided, multiple submitters, no conflicts
|
May 13, 2020 | RCV000000459.19 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Aug 24, 2023 | RCV003546449.2 |
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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Pathogenic
(May 13, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Coenzyme Q10 deficiency, primary, 5
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000917263.2
First in ClinVar: Jun 02, 2019 Last updated: Jun 08, 2020 |
Comment:
Variant summary: COQ9 c.730C>T (p.Arg244X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein … (more)
Variant summary: COQ9 c.730C>T (p.Arg244X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 1.2e-05 in 251792 control chromosomes. c.730C>T has been reported in the literature in at-least one individual affected with Autosomal-Recessive Neonatal-Onset Primary Coenzyme Q10 Deficiency (Coenzyme Q10 Deficiency, Primary, 5, Duncan_2009). These data indicate that the variant is likely to be associated with disease. Several publications report experimental evidence and mouse models evaluating an impact on protein function (example, Duncan_2009, Lopez_2010, Garcia-Corzo_2013, Luna-Sanchez_2015, Quinzii_2010). The most pronounced variant effect resulted in ~10% of the normal coenzyme Q10 biosynthesis rate (Duncan_2009), and the generation of a homozygous mouse model with the orthologous variant R239X showed a severe CoQ10 deficiency (Garcia-Corzo_2013, Hidalgo-Gutierrez_2019). One reputed database (GeneReviews) has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Mar 19, 2020)
|
criteria provided, single submitter
Method: clinical testing
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Encephalopathy-hypertrophic cardiomyopathy-renal tubular disease syndrome
Affected status: yes
Allele origin:
germline
|
Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital
Accession: SCV001984510.1
First in ClinVar: Oct 30, 2021 Last updated: Oct 30, 2021
Comment:
The Arg244* variant in COQ9 has been previously reported in the homozygous state in one individual with Coenzyme Q10 deficiency (PubMed: 19375058). This variant was … (more)
The Arg244* variant in COQ9 has been previously reported in the homozygous state in one individual with Coenzyme Q10 deficiency (PubMed: 19375058). This variant was also identified in 2/21646 (0.0092%) European Finnish alleles in the Genome Aggregation Database (gnomAD). This nonsense variant which affects the only known COQ9 transcriot leads to a premature termination codon at position 244 which is predicted to lead to a truncated or absent protein. Functional studies using fibrobalsts from patients carryring the p.Arg244* variant and a mouse model with the homologous variant at this position showed signficantly reduced levels of coenzyme Q10 (CoQ10) and several phenotypes related to this deficiency (PubMed: 23255162 20495179). In summary this variant meets our criteria to be classified as pathogenic. (less)
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Pathogenic
(Aug 24, 2023)
|
criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV004266245.1
First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Arg244*) in the COQ9 gene. It is expected to result in an absent or disrupted protein … (more)
This sequence change creates a premature translational stop signal (p.Arg244*) in the COQ9 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in COQ9 are known to be pathogenic (PMID: 19375058, 26081641). This variant is present in population databases (rs267606751, gnomAD 0.009%). This premature translational stop signal has been observed in individual(s) with coenzyme Q10 deficiency (PMID: 19375058). ClinVar contains an entry for this variant (Variation ID: 431). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Oct 01, 2010)
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no assertion criteria provided
Method: literature only
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COENZYME Q10 DEFICIENCY, PRIMARY, 5
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000020608.3
First in ClinVar: Apr 04, 2013 Last updated: Oct 14, 2016 |
Comment on evidence:
In a child of Pakistani origin with coenzyme Q10 deficiency-5 (COQ10D5; 614654), Duncan et al. (2009) identified homozygosity for a 730C-T transition in exon 7 … (more)
In a child of Pakistani origin with coenzyme Q10 deficiency-5 (COQ10D5; 614654), Duncan et al. (2009) identified homozygosity for a 730C-T transition in exon 7 of the COQ9 gene, resulting in an arg244-to-ter (R244X) mutation that truncated the terminal 75 amino acids of the protein. The mutation was absent in 308 control alleles, including 114 Pakistani controls. Arg244 of the protein is highly conserved through evolution. Site-directed mutagenesis targeting the equivalent residue in S. cerevisiae abolished respiratory growth. Quinzii et al. (2010) studied fibroblasts carrying the homozygous R244X mutation. CoQ10 levels were decreased to 18% of normal values, and cells showed impaired cell growth in galactose medium after 72 hours as well as decreased ATP levels, but no increase in reactive oxygen species or oxidative stress-induced death. Quinzii et al. (2010) concluded that the pathology caused by this mutation was related to the marked bioenergetic defect, but not to oxidative stress. The authors suggested that absence of mitochondrial respiratory activity may even confer some resistance to stress-induced apoptosis. (less)
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not provided
(-)
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no classification provided
Method: literature only
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Encephalopathy-hypertrophic cardiomyopathy-renal tubular disease syndrome
Affected status: unknown
Allele origin:
germline
|
GeneReviews
Accession: SCV000494142.2
First in ClinVar: Oct 14, 2016 Last updated: Oct 01, 2022 |
Geographic origin: Pakistan
|
Comment:
Comment:
This sequence change creates a premature translational stop signal (p.Arg244*) in the COQ9 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in COQ9 are known to be pathogenic (PMID: 19375058, 26081641). This variant is present in population databases (rs267606751, gnomAD 0.009%). This premature translational stop signal has been observed in individual(s) with coenzyme Q10 deficiency (PMID: 19375058). ClinVar contains an entry for this variant (Variation ID: 431). For these reasons, this variant has been classified as Pathogenic.
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:
Variant summary: COQ9 c.730C>T (p.Arg244X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 1.2e-05 in 251792 control chromosomes. c.730C>T has been reported in the literature in at-least one individual affected with Autosomal-Recessive Neonatal-Onset Primary Coenzyme Q10 Deficiency (Coenzyme Q10 Deficiency, Primary, 5, Duncan_2009). These data indicate that the variant is likely to be associated with disease. Several publications report experimental evidence and mouse models evaluating an impact on protein function (example, Duncan_2009, Lopez_2010, Garcia-Corzo_2013, Luna-Sanchez_2015, Quinzii_2010). The most pronounced variant effect resulted in ~10% of the normal coenzyme Q10 biosynthesis rate (Duncan_2009), and the generation of a homozygous mouse model with the orthologous variant R239X showed a severe CoQ10 deficiency (Garcia-Corzo_2013, Hidalgo-Gutierrez_2019). One reputed database (GeneReviews) has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
This sequence change creates a premature translational stop signal (p.Arg244*) in the COQ9 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in COQ9 are known to be pathogenic (PMID: 19375058, 26081641). This variant is present in population databases (rs267606751, gnomAD 0.009%). This premature translational stop signal has been observed in individual(s) with coenzyme Q10 deficiency (PMID: 19375058). ClinVar contains an entry for this variant (Variation ID: 431). For these reasons, this variant has been classified as Pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Primary Coenzyme Q(10) Deficiency Overview. | Adam MP | - | 2023 | PMID: 28125198 |
| β-RA reduces DMQ/CoQ ratio and rescues the encephalopathic phenotype in Coq9(R239X) mice. | Hidalgo-Gutiérrez A | EMBO molecular medicine | 2019 | PMID: 30482867 |
| Estimating the occurrence of primary ubiquinone deficiency by analysis of large-scale sequencing data. | Hughes BG | Scientific reports | 2017 | PMID: 29255295 |
| Human COQ9 Rescues a coq9 Yeast Mutant by Enhancing Coenzyme Q Biosynthesis from 4-Hydroxybenzoic Acid and Stabilizing the CoQ-Synthome. | He CH | Frontiers in physiology | 2017 | PMID: 28736527 |
| Fatal neonatal encephalopathy and lactic acidosis caused by a homozygous loss-of-function variant in COQ9. | Danhauser K | European journal of human genetics : EJHG | 2016 | PMID: 26081641 |
| The clinical heterogeneity of coenzyme Q10 deficiency results from genotypic differences in the Coq9 gene. | Luna-Sánchez M | EMBO molecular medicine | 2015 | PMID: 25802402 |
| Dysfunctional Coq9 protein causes predominant encephalomyopathy associated with CoQ deficiency. | García-Corzo L | Human molecular genetics | 2013 | PMID: 23255162 |
| Heterogeneity of coenzyme Q10 deficiency: patient study and literature review. | Emmanuele V | Archives of neurology | 2012 | PMID: 22490322 |
| Treatment of CoQ(10) deficient fibroblasts with ubiquinone, CoQ analogs, and vitamin C: time- and compound-dependent effects. | López LC | PloS one | 2010 | PMID: 20689595 |
| Reactive oxygen species, oxidative stress, and cell death correlate with level of CoQ10 deficiency. | Quinzii CM | FASEB journal : official publication of the Federation of American Societies for Experimental Biology | 2010 | PMID: 20495179 |
| A nonsense mutation in COQ9 causes autosomal-recessive neonatal-onset primary coenzyme Q10 deficiency: a potentially treatable form of mitochondrial disease. | Duncan AJ | American journal of human genetics | 2009 | PMID: 19375058 |
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Text-mined citations for rs267606751 ...
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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 Nov 25, 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.