1-226982954-C-T

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM1PM2PP3PP5

The NM_020247.5(COQ8A):c.1000C>T(p.Arg334Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000535 in 1,607,472 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R334Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 34)

Exomes 𝑓: 0.000054 ( 0 hom. )

Consequence

COQ8A
NM_020247.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:1

Conservation

PhyloP100: 1.88

Publications

2 publications found

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 Gene-Disease associations (from GenCC):

autosomal recessive ataxia due to ubiquinone deficiency
Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, G2P
coenzyme Q10 deficiency
Inheritance: AR Classification: DEFINITIVE Submitted by: Illumina

COQ8A links:

ENSG00000288674 (HGNC:):

ENSG00000288674 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 9 uncertain in NM_020247.5

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.754

PP5

Variant 1-226982954-C-T is Pathogenic according to our data. Variant chr1-226982954-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 434088. Variant chr1-226982954-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 434088. Variant chr1-226982954-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 434088. Variant chr1-226982954-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 434088. Variant chr1-226982954-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 434088. Variant chr1-226982954-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 434088. Variant chr1-226982954-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 434088. Variant chr1-226982954-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 434088. Variant chr1-226982954-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 434088. Variant chr1-226982954-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 434088. Variant chr1-226982954-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 434088. Variant chr1-226982954-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 434088. Variant chr1-226982954-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 434088. Variant chr1-226982954-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 434088. Variant chr1-226982954-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 434088. Variant chr1-226982954-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 434088. Variant chr1-226982954-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 434088. Variant chr1-226982954-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 434088. Variant chr1-226982954-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 434088. Variant chr1-226982954-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 434088. Variant chr1-226982954-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 434088. Variant chr1-226982954-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 434088. Variant chr1-226982954-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 434088. Variant chr1-226982954-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 434088. Variant chr1-226982954-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 434088. Variant chr1-226982954-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 434088. Variant chr1-226982954-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 434088. Variant chr1-226982954-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 434088. Variant chr1-226982954-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 434088. Variant chr1-226982954-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 434088. Variant chr1-226982954-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 434088. Variant chr1-226982954-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 434088. Variant chr1-226982954-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 434088. Variant chr1-226982954-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 434088. Variant chr1-226982954-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 434088. Variant chr1-226982954-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 434088. Variant chr1-226982954-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 434088. Variant chr1-226982954-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 434088. Variant chr1-226982954-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 434088. Variant chr1-226982954-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 434088. Variant chr1-226982954-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 434088. Variant chr1-226982954-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 434088. Variant chr1-226982954-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 434088. Variant chr1-226982954-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 434088. Variant chr1-226982954-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 434088. Variant chr1-226982954-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 434088. Variant chr1-226982954-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 434088. Variant chr1-226982954-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 434088. Variant chr1-226982954-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 434088. Variant chr1-226982954-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 434088. Variant chr1-226982954-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 434088. Variant chr1-226982954-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 434088. Variant chr1-226982954-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 434088. Variant chr1-226982954-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 434088. Variant chr1-226982954-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 434088. Variant chr1-226982954-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 434088. Variant chr1-226982954-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 434088. Variant chr1-226982954-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 434088. Variant chr1-226982954-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 434088. Variant chr1-226982954-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 434088. Variant chr1-226982954-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 434088. Variant chr1-226982954-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 434088. Variant chr1-226982954-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 434088. Variant chr1-226982954-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 434088. Variant chr1-226982954-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 434088. Variant chr1-226982954-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 434088. Variant chr1-226982954-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 434088. Variant chr1-226982954-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 434088. Variant chr1-226982954-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 434088. Variant chr1-226982954-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 434088. Variant chr1-226982954-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 434088. Variant chr1-226982954-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 434088. Variant chr1-226982954-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 434088.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COQ8A	NM_020247.5 link	c.1000C>T	p.Arg334Trp	missense_variant	Exon 8 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.1000C>T	p.Arg334Trp	missense_variant	Exon 8 of 15	1	NM_020247.5	ENSP00000355739.3	Q8NI60-1
ENSG00000288674	ENST00000366779.6 link	n.*5727C>T		non_coding_transcript_exon_variant	Exon 25 of 32	2		ENSP00000355741.2
ENSG00000288674	ENST00000366779.6 link	n.*5727C>T		3_prime_UTR_variant	Exon 25 of 32	2		ENSP00000355741.2

Frequencies

GnomAD3 genomes

AF:

0.0000525

AC:

AN:

152254

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.000103

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000635

AC:

AN:

236112

AF XY:

0.0000620

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000116

Gnomad FIN exome

AF:

0.0000491

Gnomad NFE exome

AF:

0.000105

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000536

AC:

AN:

1455100

Hom.:

Cov.:

AF XY:

0.0000567

AC XY:

AN XY:

723546

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33324

American (AMR)

AF:

0.00

AC:

AN:

44138

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26054

East Asian (EAS)

AF:

0.0000255

AC:

AN:

39262

South Asian (SAS)

AF:

0.0000117

AC:

AN:

85652

European-Finnish (FIN)

AF:

0.0000390

AC:

AN:

51332

Middle Eastern (MID)

AF:

0.000175

AC:

AN:

5708

European-Non Finnish (NFE)

AF:

0.0000631

AC:

AN:

1109572

Other (OTH)

AF:

0.0000500

AC:

AN:

60058

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000525

AC:

AN:

152372

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74508

show subpopulations

African (AFR)

AF:

0.0000240

AC:

AN:

41600

American (AMR)

AF:

0.00

AC:

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5174

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000103

AC:

AN:

68040

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000675

Hom.:

Bravo

AF:

0.0000604

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000663

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:1Uncertain:1

Dec 22, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 334 of the COQ8A protein (p.Arg334Trp). This variant is present in population databases (rs373971613, gnomAD 0.01%). This missense change has been observed in individual(s) with clinical features of primary coenzyme Q10 deficiency and/or clinical features of primary coenzyme Q10 deficiency (PMID: 29915382). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 434088). 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 COQ8A protein function. 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. -

May 17, 2024

GeneDx

Significance:Uncertain significance

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: 29915382) -

Autosomal recessive ataxia due to ubiquinone deficiency

Pathogenic:1

Feb 07, 2017

Genetic Services Laboratory, University of Chicago

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

Benign

0.22

BayesDel_addAF

Benign

-0.057

BayesDel_noAF

Benign

-0.090

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.58

D;.;D

Eigen

Uncertain

0.68

Eigen_PC

Uncertain

0.63

FATHMM_MKL

Uncertain

0.83

LIST_S2

Pathogenic

0.99

.;D;D

M_CAP

Benign

0.048

MetaRNN

Pathogenic

0.75

D;D;D

MetaSVM

Uncertain

-0.26

PhyloP100

1.9

PrimateAI

Uncertain

0.75

PROVEAN

Pathogenic

-5.3

D;D;D

REVEL

Benign

0.29

Sift

Uncertain

0.0040

D;D;D

Sift4G

Uncertain

0.0030

D;D;D

Polyphen

1.0

D;.;D

Vest4

0.72

MVP

0.91

MPC

0.26

ClinPred

0.87

GERP RS

4.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Varity_R

0.90

gMVP

0.77

Mutation Taster

=6/94

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over