VCV000003645.63 - ClinVar

NM_020247.5(COQ8A):c.993C>T (p.Phe331=)

Germline

Classification

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.

(18)

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.

Benign/Likely benign

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_020247.5(COQ8A):c.993C>T (p.Phe331=)

Variation ID: 3645 Accession: VCV000003645.63

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 1q42.13 1: 226982947 (GRCh38) [ NCBI UCSC ] 1: 227170648 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	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 11, 2015	Oct 20, 2024	Aug 1, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_020247.5:c.993C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_064632.2:p.Phe331=	synonymous
NC_000001.11:g.226982947C>T
NC_000001.10:g.227170648C>T
NG_012825.2:g.90412C>T
LRG_1092:g.90412C>T
LRG_1092t1:c.993C>T	LRG_1092p1:p.Phe331=

... more HGVS ... less HGVS

Protein change

Other names

p.F331F:TTC>TTT

Canonical SPDI

NC_000001.11:226982946:C:T

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The 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.

0.00559 (T)

Allele frequency Help The frequency of the allele represented by this VCV record.

1000 Genomes Project 0.00559

1000 Genomes Project 30x 0.00562

Trans-Omics for Precision Medicine (TOPMed) 0.01261

The Genome Aggregation Database (gnomAD) 0.01390

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.01500

The Genome Aggregation Database (gnomAD), exomes 0.01566

Exome Aggregation Consortium (ExAC) 0.02091

Links

ClinGen: CA116409 OMIM: 606980.0010 dbSNP: rs41303129 VarSome

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
Gene	OMIM	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.
COQ8A		-	-	GRCh38 GRCh37	719	763

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.
Autosomal recessive ataxia due to ubiquinone deficiency	Benign (5)	criteria provided, multiple submitters, no conflicts	Jun 28, 2023	RCV000003830.23
not provided	Benign/Likely benign (6)	criteria provided, multiple submitters, no conflicts	Aug 1, 2024	RCV000415784.36
not specified	Benign (5)	criteria provided, multiple submitters, no conflicts	Mar 29, 2016	RCV000180351.13
Joubert syndrome 17	Benign (1)	criteria provided, single submitter	-	RCV001258271.3
Coenzyme Q10 deficiency	Benign (1)	criteria provided, single submitter	Jun 6, 2023	RCV003993734.1

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.
Benign (Apr 12, 2015)	criteria provided, single submitter (DGD Variant Analysis Guidelines) Method: clinical testing	not specified Affected status: unknown Allele origin: unknown	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia Accession: SCV000258150.2 First in ClinVar: Oct 11, 2015 Last updated: Oct 11, 2015
Benign (Mar 29, 2016)	criteria provided, single submitter (LMM Criteria) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV000538237.1 First in ClinVar: Oct 11, 2015 Last updated: Oct 11, 2015	Comment: Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or … (more) Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: frequency in ExAC 2.8% in european population with (24 homozygotes). Also Benign in Clinvar (by GeneDx and Emory) (less) Method: Genome/Exome Filtration
Benign (Dec 17, 2014)	criteria provided, single submitter (EGL Classification Definitions 2015) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000232764.5 First in ClinVar: Jun 28, 2015 Last updated: Oct 11, 2015	Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=COQ8A Number of individuals with the variant: 1 Sex: mixed
Benign (Jul 20, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Autosomal recessive ataxia due to ubiquinone deficiency Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV002803569.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022
Benign (Jan 31, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV001724874.4 First in ClinVar: Jun 15, 2021 Last updated: Feb 20, 2024
Benign (Jun 28, 2023)	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2024) Method: clinical testing	Autosomal recessive ataxia due to ubiquinone deficiency Affected status: unknown Allele origin: germline	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories Accession: SCV000884981.5 First in ClinVar: Aug 04, 2018 Last updated: Feb 20, 2024
Likely benign (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: not provided	not provided (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Breakthrough Genomics, Breakthrough Genomics Accession: SCV005263836.1 First in ClinVar: Sep 29, 2024 Last updated: Sep 29, 2024
Benign (Aug 01, 2024)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV000493421.33 First in ClinVar: Jan 30, 2017 Last updated: Oct 20, 2024	Comment: COQ8A: BP4, BP7, BS1, BS2 Number of individuals with the variant: 52
Benign (Mar 06, 2018)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Autosomal recessive ataxia due to ubiquinone deficiency Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000355249.3 First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020	Comment: This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated … (more) This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. (less)
Benign (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Joubert syndrome 17 (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard Accession: SCV001435196.1 First in ClinVar: Oct 03, 2020 Last updated: Oct 03, 2020	Comment: The c.993C>T (p.Phe331=) variant in ADCK3 has been identified in a French and Algerian individual with ubiquinone deficiency with cerebellar ataxia (PMID: 18319074), but has … (more) The c.993C>T (p.Phe331=) variant in ADCK3 has been identified in a French and Algerian individual with ubiquinone deficiency with cerebellar ataxia (PMID: 18319074), but has also been identified in >4% of European (Finnish) chromosomes and 33 homozygotes by ExAC (http://gnomad.broadinstitute.org/). In vitro functional studies provide some evidence that the c.993C>T variant may not impact protein function (PMID: 18319074). However, these types of assays may not accurately represent biological function. In summary, this variant meets criteria to be classified as benign for autosomal recessive ubiquinone deficiency with cerebellar ataxia. (less)
Benign (Dec 04, 2018)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000166878.12 First in ClinVar: Jun 23, 2014 Last updated: Oct 11, 2015	Comment: This variant is associated with the following publications: (PMID: 26764160, 27884173, 27535533, 18319074, 32337771)
Benign (Jun 06, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Coenzyme Q10 deficiency (Autosomal recessive inheritance) Affected status: no Allele origin: germline	Molecular Genetics, Royal Melbourne Hospital Additional submitter: Shariant Australia, Australian Genomics Accession: SCV004812795.1 First in ClinVar: Apr 15, 2024 Last updated: Apr 15, 2024
Pathogenic (Mar 01, 2008)	no assertion criteria provided Method: literature only	COENZYME Q10 DEFICIENCY, PRIMARY, 4 Affected status: not provided Allele origin: germline	OMIM Accession: SCV000023995.3 First in ClinVar: Apr 04, 2013 Last updated: Nov 06, 2016	Publications: PubMed (1) PubMed: 18319074 Comment on evidence: In a patient of French and Algerian ancestry with CoQ10 deficiency-4 manifest as cerebellar ataxia (COQ10D4; 612016), Lagier-Tourenne et al. (2008) found compound heterozygosity for … (more) In a patient of French and Algerian ancestry with CoQ10 deficiency-4 manifest as cerebellar ataxia (COQ10D4; 612016), Lagier-Tourenne et al. (2008) found compound heterozygosity for 2 mutations in the ADCK3 gene: a mutation in a predicted exonic splice enhancer in exon 8 (993C-T), and a 1645G-A transition in exon 14, resulting in a gly549-to-ser substitution (G549S; 606980.0011). The exon 8 mutation resulted in skipping of exon 8 leading to an in-frame deletion of 47 amino acids (Lys314_Gln360del). (less)
Benign (-)	no assertion criteria provided Method: clinical testing	not specified Affected status: yes Allele origin: germline	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001742409.3 First in ClinVar: Jul 07, 2021 Last updated: Sep 08, 2021
Likely benign (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Genome Diagnostics Laboratory, University Medical Center Utrecht Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001931737.1 First in ClinVar: Sep 26, 2021 Last updated: Sep 26, 2021
Benign (Feb 25, 2016)	no assertion criteria provided Method: clinical testing	not provided Affected status: unknown Allele origin: unknown	Mayo Clinic Laboratories, Mayo Clinic Accession: SCV000801931.1 First in ClinVar: Aug 04, 2018 Last updated: Aug 04, 2018
Benign (-)	no assertion criteria provided Method: clinical testing	not specified Affected status: yes Allele origin: germline	Clinical Genetics, Academic Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001924656.1 First in ClinVar: Sep 26, 2021 Last updated: Sep 26, 2021
not provided (-)	no classification provided Method: literature only	Autosomal recessive ataxia due to ubiquinone deficiency Affected status: unknown Allele origin: germline	GeneReviews Accession: SCV000494096.2 First in ClinVar: Nov 10, 2016 Last updated: Oct 01, 2022 Comment: Causes the skipping of exon 8 leading to an in-frame deletion of 47 amino acids (p.Lys314_Gln360del) .	Publications: PubMed (1) PubMed: 18319074 BookShelf: NBK410087 BookShelf: NBK410087
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Comment:

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: frequency in ExAC 2.8% in european population with (24 homozygotes). Also Benign in Clinvar (by GeneDx and Emory)

Comment:

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

Comment:

The c.993C>T (p.Phe331=) variant in ADCK3 has been identified in a French and Algerian individual with ubiquinone deficiency with cerebellar ataxia (PMID: 18319074), but has also been identified in >4% of European (Finnish) chromosomes and 33 homozygotes by ExAC (http://gnomad.broadinstitute.org/). In vitro functional studies provide some evidence that the c.993C>T variant may not impact protein function (PMID: 18319074). However, these types of assays may not accurately represent biological function. In summary, this variant meets criteria to be classified as benign for autosomal recessive ubiquinone deficiency with cerebellar ataxia.

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:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Primary Coenzyme Q(10) Deficiency Overview.	Adam MP	-	2023	PMID: 28125198
ADCK3, an ancestral kinase, is mutated in a form of recessive ataxia associated with coenzyme Q10 deficiency.	Lagier-Tourenne C	American journal of human genetics	2008	PMID: 18319074
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=COQ8A	-	-	-	-

Text-mined citations for rs41303129 ...

These 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 Oct 20, 2024

ClinVar Genomic variation as it relates to human health

NM_020247.5(COQ8A):c.993C>T (p.Phe331=)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs41303129 ...