ClinVar Genomic variation as it relates to human health
NM_016035.5(COQ4):c.718C>T (p.Arg240Cys)
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_016035.5(COQ4):c.718C>T (p.Arg240Cys)
Variation ID: 189201 Accession: VCV000189201.21
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 9q34.11 9: 128333565 (GRCh38) [ NCBI UCSC ] 9: 131095844 (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 30, 2016 Feb 14, 2024 Jan 18, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_016035.5:c.718C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_057119.3:p.Arg240Cys missense NM_001305942.2:c.*94C>T 3 prime UTR NC_000009.12:g.128333565C>T NC_000009.11:g.131095844C>T NG_042101.1:g.16058C>T Q9Y3A0:p.Arg240Cys NP_057119.2:p.Arg240Cys - Protein change
- R240C
- Other names
- COQ4, ARG240CYS (rs143441644)
- Canonical SPDI
- NC_000009.12:128333564: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.
Exome Aggregation Consortium (ExAC) 0.00024
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00031
The Genome Aggregation Database (gnomAD) 0.00017
Trans-Omics for Precision Medicine (TOPMed) 0.00017
The Genome Aggregation Database (gnomAD), exomes 0.00020
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
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. |
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COQ4 | - | - |
GRCh38 GRCh37 |
265 | 324 |
Conditions - Germline
Condition
Help
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
Help
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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Pathogenic/Likely pathogenic (7) |
criteria provided, multiple submitters, no conflicts
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Jan 18, 2024 | RCV000169636.21 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Mar 29, 2023 | RCV000256139.8 | |
Pathogenic (1) |
criteria provided, single submitter
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Jan 4, 2021 | RCV001640262.1 | |
Pathogenic (1) |
criteria provided, single submitter
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May 5, 2022 | RCV002515203.1 | |
Pathogenic (1) |
criteria provided, single submitter
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Jun 8, 2023 | RCV003390884.4 |
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
(Oct 19, 2017)
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criteria provided, single submitter
Method: clinical testing
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Neonatal encephalomyopathy-cardiomyopathy-respiratory distress syndrome
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
maternal
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Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München
Accession: SCV000680182.1
First in ClinVar: Feb 08, 2018 Last updated: Feb 08, 2018 |
Sex: female
Tissue: blood
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Pathogenic
(Jan 04, 2021)
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criteria provided, single submitter
Method: research
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Spastic ataxia
Affected status: yes
Allele origin:
inherited
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Molecular Medicine for Neurodegenerative and Neuromuscular Diseases Unit, IRCCS Fondazione Stella Maris
Accession: SCV001519121.1
First in ClinVar: Sep 19, 2021 Last updated: Sep 19, 2021 |
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Likely pathogenic
(Aug 27, 2021)
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criteria provided, single submitter
Method: clinical testing
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Neonatal encephalomyopathy-cardiomyopathy-respiratory distress syndrome
Affected status: unknown
Allele origin:
inherited
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New York Genome Center
Study: CSER-NYCKidSeq
Accession: SCV002564361.1 First in ClinVar: Aug 23, 2022 Last updated: Aug 23, 2022 |
Clinical Features:
Intellectual disability (present) , Global developmental delay (present) , Hypotonia (present) , Speech apraxia (present) , Attention deficit hyperactivity disorder (present) , Seizure (present)
Secondary finding: no
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Likely pathogenic
(Sep 28, 2021)
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criteria provided, single submitter
Method: clinical testing
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Neonatal encephalomyopathy-cardiomyopathy-respiratory distress syndrome
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV002816427.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Pathogenic
(May 05, 2022)
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criteria provided, single submitter
Method: clinical testing
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Inborn genetic diseases
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV003758080.1
First in ClinVar: Feb 07, 2023 Last updated: Feb 07, 2023 |
Comment:
The c.718C>T (p.R240C) alteration is located in exon 7 (coding exon 7) of the COQ4 gene. This alteration results from a C to T substitution … (more)
The c.718C>T (p.R240C) alteration is located in exon 7 (coding exon 7) of the COQ4 gene. This alteration results from a C to T substitution at nucleotide position 718, causing the arginine (R) at amino acid position 240 to be replaced by a cysteine (C). Based on data from gnomAD, the T allele has an overall frequency of 0.02% (50/278786) total alleles studied. The highest observed frequency was 0.34% (35/10230) of Ashkenazi Jewish alleles. This alteration has been detected in the homozygous state and in trans with other pathogenic COQ4 alterations in multiple individuals with COQ4-related primary coenzyme Q10 deficiency (Brea-Calvo, 2015; Chung, 2015; de Castro, 2020; Galatolo, 2021; Mero, 2021; Barbosa-Gouveia, 2021). This amino acid position is highly conserved in available vertebrate species. In functional studies involving a recombinant yeast model, human COQ4 with the R240C variant was unable to rescue loss of yeast COQ4 (Brea-Calvo, 2015). The in silico prediction for this alteration is inconclusive. Based on the available evidence, this alteration is classified as pathogenic. (less)
Number of individuals with the variant: 1
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Pathogenic
(Nov 10, 2022)
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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: SCV000321520.10
First in ClinVar: Oct 10, 2016 Last updated: Mar 04, 2023 |
Comment:
Functional studies find that p.(R240C) significantly impairs oxidative growth in a recombinant yeast model (Brea-Calvo G et al., 2015).; In silico analysis supports that this … (more)
Functional studies find that p.(R240C) significantly impairs oxidative growth in a recombinant yeast model (Brea-Calvo G et al., 2015).; 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: 26185144, 25658047, 28540186, 33704555, 34440436, 31589614, 32746448, 33726816, 31967322, 29255295, 32718099, 30642647) (less)
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Pathogenic
(Jun 08, 2023)
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criteria provided, single submitter
Method: clinical testing
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COQ4-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004120574.1
First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023 |
Comment:
The COQ4 c.718C>T variant is predicted to result in the amino acid substitution p.Arg240Cys. This variant was found in the homozygous and compound heterozygous state … (more)
The COQ4 c.718C>T variant is predicted to result in the amino acid substitution p.Arg240Cys. This variant was found in the homozygous and compound heterozygous state in multiple affected individuals with Coenzyme Q10 deficiency (see for example Brea-Calvo et al. 2015. PubMed ID: 25658047, Chung et al. 2015. PubMed ID: 26185144, de Castro et al. 2020. PubMed ID: 32718099). This variant is reported in 0.34% of alleles in individuals of Ashkenazi Jewish descent in gnomAD (http://gnomad.broadinstitute.org/variant/9-131095844-C-T). Functional characterization suggests that this variant has a deleterious effect on the protein (Brea-Calvo et al. 2015. PubMed ID: 25658047). This variant is interpreted as pathogenic. (less)
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Pathogenic
(Mar 29, 2023)
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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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Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV004227151.1
First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024 |
Comment:
PP3, PM2_strong, PM3_strong, PS3, PS4_moderate
Number of individuals with the variant: 1
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Likely pathogenic
(Jun 02, 2023)
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criteria provided, single submitter
Method: clinical testing
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Neonatal encephalomyopathy-cardiomyopathy-respiratory distress syndrome
Affected status: unknown
Allele origin:
germline
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Revvity Omics, Revvity
Accession: SCV004238555.1
First in ClinVar: Feb 04, 2024 Last updated: Feb 04, 2024 |
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Pathogenic
(Jan 18, 2024)
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criteria provided, single submitter
Method: clinical testing
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Neonatal encephalomyopathy-cardiomyopathy-respiratory distress syndrome
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000828752.4
First in ClinVar: Oct 10, 2018 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 240 of the COQ4 protein … (more)
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 240 of the COQ4 protein (p.Arg240Cys). This variant is present in population databases (rs143441644, gnomAD 0.3%). This missense change has been observed in individual(s) with COQ4-related conditions (PMID: 25658047, 26185144, 32718099, 33704555). 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: 189201). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on COQ4 protein function. Experimental studies have shown that this missense change affects COQ4 function (PMID: 26185144, 33704555). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Feb 05, 2015)
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no assertion criteria provided
Method: literature only
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COENZYME Q10 DEFICIENCY, PRIMARY, 7
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000221165.3
First in ClinVar: Mar 29, 2015 Last updated: Apr 24, 2021 |
Comment on evidence:
For discussion of the c.718C-T transition (rs143441644) in exon 7 of the COQ4 gene, resulting in an arg240-to-cys (R240C) substitution, that was found in compound … (more)
For discussion of the c.718C-T transition (rs143441644) in exon 7 of the COQ4 gene, resulting in an arg240-to-cys (R240C) substitution, that was found in compound heterozygous state in a patient with primary coenzyme Q10 deficiency-7 (COQ10D7; 616276) by Brea-Calvo et al. (2015), see 612898.0002. In 2 unrelated girls of Ashkenazi Jewish descent with COQ10D7, Chung et al. (2015) identified homozygosity for the c.718C-T transition in the COQ4 gene, resulting in an R240C substitution. The mutation, which was found by exome sequencing, segregated with the disorder in both families. The variant was found at a frequency of 1 in 2,420 among Europeans in the ExAC database and of 1 in 2,149 among Europeans in the Exome Sequencing Project database. Among 1,047 Ashkenazi Jewish controls, there was a carrier frequency of 1 in 150 and an allele frequency of 1 in 300, consistent with a founder effect in this population. Functional studies of the variant and studies of patient cells were not performed; both patients died in early infancy. In a 30-month-old boy with COQ10D7, Mero et al. (2021) identified compound heterozygous mutations in the COQ4 gene: R240C and a c.577C-T transition resulting in a pro193-to-ser (P193S; 612898.0009) substitution. The mutations were identified by next-generation sequencing of a panel of 273 genes linked to hereditary ataxias. The P193S mutation was not present in the gnomAD database, and the R240C was present at a frequency of 0.000179. Yeast expressing COQ4 with the R240C or P193S mutation failed to grow when plated in nonfermentable medium. (less)
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not provided
(-)
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no classification provided
Method: literature only
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Neonatal encephalomyopathy-cardiomyopathy-respiratory distress syndrome
Affected status: unknown
Allele origin:
germline
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GeneReviews
Accession: SCV000494133.2
First in ClinVar: Nov 10, 2016 Last updated: Oct 01, 2022 |
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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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Primary Coenzyme Q(10) Deficiency Overview. | Adam MP | - | 2023 | PMID: 28125198 |
NGS in Hereditary Ataxia: When Rare Becomes Frequent. | Galatolo D | International journal of molecular sciences | 2021 | PMID: 34445196 |
Utility of Gene Panels for the Diagnosis of Inborn Errors of Metabolism in a Metabolic Reference Center. | Barbosa-Gouveia S | Genes | 2021 | PMID: 34440436 |
New pathogenic variants in COQ4 cause ataxia and neurodevelopmental disorder without detectable CoQ(10) deficiency in muscle or skin fibroblasts. | Mero S | Journal of neurology | 2021 | PMID: 33704555 |
Rapid Phenotype-Driven Gene Sequencing with the NeoSeq Panel: A Diagnostic Tool for Critically Ill Newborns with Suspected Genetic Disease. | de Castro MJ | Journal of clinical medicine | 2020 | PMID: 32718099 |
Mortality of Japanese patients with Leigh syndrome: Effects of age at onset and genetic diagnosis. | Ogawa E | Journal of inherited metabolic disease | 2020 | PMID: 31967322 |
Mutations in COQ4, an essential component of coenzyme Q biosynthesis, cause lethal neonatal mitochondrial encephalomyopathy. | Chung WK | Journal of medical genetics | 2015 | PMID: 26185144 |
COQ4 mutations cause a broad spectrum of mitochondrial disorders associated with CoQ10 deficiency. | Brea-Calvo G | American journal of human genetics | 2015 | PMID: 25658047 |
Text-mined citations for rs143441644 ...
HelpRecord last updated Apr 20, 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.