1-226982735-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM1PM2PM5PP3PP5_Very_Strong

The NM_020247.5(COQ8A):c.911C>T(p.Ala304Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000403 in 1,613,568 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A304T) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000042 ( 0 hom. )

Consequence

COQ8A
NM_020247.5 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8

Conservation

PhyloP100: 7.77

Variant links:

Genes affected

COQ8A (HGNC:16812): (coenzyme Q8A) This gene encodes a mitochondrial protein similar to yeast ABC1, which functions in an electron-transferring membrane protein complex in the respiratory chain. It is not related to the family of ABC transporter proteins. Expression of this gene is induced by the tumor suppressor p53 and in response to DNA damage, and inhibiting its expression partially suppresses p53-induced apoptosis. Alternatively spliced transcript variants have been found; however, their full-length nature has not been determined. [provided by RefSeq, Jul 2008]

COQ8A links:

ENSG00000288674 (HGNC:):

ENSG00000288674 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 15 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_020247.5

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr1-226982734-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2202994.Status of the report is criteria_provided_single_submitter, 1 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.837

PP5

Variant 1-226982735-C-T is Pathogenic according to our data. Variant chr1-226982735-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 381728.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COQ8A	NM_020247.5 link	c.911C>T	p.Ala304Val	missense_variant	Exon 7 of 15	ENST00000366777.4	NP_064632.2	Q8NI60-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
COQ8A	ENST00000366777.4 link	c.911C>T	p.Ala304Val	missense_variant	Exon 7 of 15	1	NM_020247.5	ENSP00000355739.3	Q8NI60-1
ENSG00000288674	ENST00000366779.6 link	n.*5638C>T		non_coding_transcript_exon_variant	Exon 24 of 32	2		ENSP00000355741.2
ENSG00000288674	ENST00000366779.6 link	n.*5638C>T		3_prime_UTR_variant	Exon 24 of 32	2		ENSP00000355741.2

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152194

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000399

AC:

AN:

250734

Hom.:

AF XY:

0.0000516

AC XY:

AN XY:

135788

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000795

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000424

AC:

AN:

1461374

Hom.:

Cov.:

AF XY:

0.0000495

AC XY:

AN XY:

726972

show subpopulations

Gnomad4 AFR exome

AF:

0.0000896

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000477

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152194

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74346

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000611

Hom.:

Bravo

AF:

0.00000756

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.000119

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:4

Dec 04, 2023

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); 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: 29482223, 27106809, 22036850, 33622667, 37476682, 32337771, 27142713, 35872528, 33949708, 29255295, 34638552, 33677064) -

Apr 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

COQ8A: PM2, PM3, PM5, PP3 -

Dec 16, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 304 of the COQ8A protein (p.Ala304Val). This variant is present in population databases (rs748118737, gnomAD 0.008%). This missense change has been observed in individuals with clinical features of coenzyme Q10 deficiency (PMID: 22036850, 27142713, 29482223, 33949708, 37476682). ClinVar contains an entry for this variant (Variation ID: 381728). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt COQ8A protein function with a positive predictive value of 80%. This variant disrupts the p.Ala304 amino acid residue in COQ8A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 22036850; internal data). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Jun 03, 2024

Athena Diagnostics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The frequency of this variant in the general population is consistent with pathogenicity. (http://gnomad.broadinstitute.org) This variant has been identified homozygous in multiple unrelated individuals with clinical features associated with this gene. Polyphen and MutationTaster predict this amino acid change may be damaging to the protein. -

Autosomal recessive ataxia due to ubiquinone deficiency

Pathogenic:4

May 20, 2023

Neuberg Centre For Genomic Medicine, NCGM

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The observed missense c.911C>T(p.Ala304Val) variant in COQ8A gene has been reported previously in homozygous and compound heterozygous state in individuals affected with coenzyme Q deficiency (Hughes BG, et al., 2017; Horvath R, et al., 2012). The p.Ala304Val variant has been reported with allele frequency of 0.004% in gnomAD Exomes. This variant has been reported to the ClinVar database as Uncertain Significance / Likely Pathogenic (multiple submissions). Multiple lines of computational evidences (Polyphen - Probably damaging, SIFT - Damaging and MutationTaster - Disease causing) predict a damaging effect on protein structure and function for this variant. The amino acid change p.Ala304Val in COQ8A is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Ala at position 304 is changed to a Val changing protein sequence and it might alter its composition and physico-chemical properties. Another missense variant [c.910G>A p.Ala304Thr] on the same residue of this gene has previously been reported to be disease causing (Horvath R, et al., 2012), suggesting that this residue might be of clinical significance. However, additional functional studies will be required to prove the pathogenicity of this variant. For these reasons, this variant has been classified as Likely Pathogenic. Another significant variant [c.215A>G p.Gln72Arg] in COQ8A gene has been identified in heterozygous state in the spouse. -

May 07, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 26, 2020

Molecular Genetics, Royal Melbourne Hospital

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change is predicted to replace alanine with valine at codon 304 of the COQ8A protein (p.Ala304Val). The alanine residue is highly conserved (100 vertebrates, UCSC), and is located in an alpha-helix. There is a small physicochemical difference between alanine and valine, but the substitution is predicted to cause a steric clash with Pro335 and Ala338 (PMID: 25498144). The variant is present in a large population cohort at a frequency of 0.004%, which is consistent with recessive conditions (rs748118737, 11/282,096 alleles, 0 homozygotes in gnomAD v2.1). It has been identified in the homozygous state in two unrelated individuals with cerebellar ataxia (PMID: 22036850, 27142713). In one of these individuals non-genetic biochemical tests in a muscle biopsy were conducted to confirm coenzyme Q10 deficiency, and showed combined respiratory chain deficiency and significantly decreased coenzyme Q10 (PMID: 22036850). Multiple lines of computational evidence predict a deleterious effect for the missense substitution (6/7 algorithms). Additionally, another missense substitution at this position (p.Ala304Thr) has been identified in an individual with cerebellar ataxia (PMID: 22036850). Based on the classification scheme RMH ACMG Guidelines v1.1.1, this variant is classified as LIKELY PATHOGENIC. Following criteria are met: PM2, PM3, PP3, PP4. -

Aug 17, 2020

Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.96

BayesDel_addAF

Pathogenic

0.28

BayesDel_noAF

Pathogenic

0.36

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.56

D;.;D

Eigen

Pathogenic

0.83

Eigen_PC

Uncertain

0.66

FATHMM_MKL

Uncertain

0.96

LIST_S2

Pathogenic

1.0

.;D;D

M_CAP

Uncertain

0.24

MetaRNN

Pathogenic

0.84

D;D;D

MetaSVM

Pathogenic

0.84

PrimateAI

Pathogenic

0.81

PROVEAN

Uncertain

-3.8

D;D;D

REVEL

Pathogenic

0.71

Sift

Uncertain

0.0010

D;D;D

Sift4G

Uncertain

0.0020

D;D;D

Polyphen

1.0

D;.;D

Vest4

0.94

MutPred

0.37

Gain of MoRF binding (P = 0.1474);.;Gain of MoRF binding (P = 0.1474);

MVP

0.94

MPC

0.30

ClinPred

0.99

GERP RS

5.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Varity_R

0.65

gMVP

0.69

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over