1-226982107-C-T

Position:

chr1-226982107-C-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2PP3_ModeratePP5_Very_Strong

The NM_020247.5(COQ8A):c.811C>T(p.Arg271Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000447 in 1,609,714 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 (★★).

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000045 ( 0 hom. )

Consequence

COQ8A
NM_020247.5 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8U:2O:2

Conservation

PhyloP100: 3.24

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:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.873

PP5

Variant 1-226982107-C-T is Pathogenic according to our data. Variant chr1-226982107-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 296015.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COQ8A	NM_020247.5 linkuse as main transcript	c.811C>T	p.Arg271Cys	missense_variant	6/15	ENST00000366777.4	NP_064632.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COQ8A	ENST00000366777.4 linkuse as main transcript	c.811C>T	p.Arg271Cys	missense_variant	6/15	1	NM_020247.5	ENSP00000355739	P1	Q8NI60-1
COQ8A	ENST00000366778.5 linkuse as main transcript	c.655C>T	p.Arg219Cys	missense_variant	6/15	1		ENSP00000355740		Q8NI60-3
COQ8A	ENST00000485462.5 linkuse as main transcript	n.201C>T		non_coding_transcript_exon_variant	2/11	1
COQ8A	ENST00000478406.5 linkuse as main transcript	n.262C>T		non_coding_transcript_exon_variant	3/8	2

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152154

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:

0.000283

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000103

AC:

AN:

241910

Hom.:

AF XY:

0.000122

AC XY:

AN XY:

131670

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:

0.000808

Gnomad NFE exome

AF:

0.0000645

Gnomad OTH exome

AF:

0.000168

GnomAD4 exome

AF:

0.0000446

AC:

AN:

1457560

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

724816

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000636

Gnomad4 NFE exome

AF:

0.0000252

Gnomad4 OTH exome

AF:

0.0000664

GnomAD4 genome

AF:

0.0000460

AC:

AN:

152154

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74316

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:

0.000283

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000345

Hom.:

Bravo

AF:

0.0000189

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000909

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8Uncertain:2Other:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Autosomal recessive ataxia due to ubiquinone deficiency

Pathogenic:4Uncertain:1Other:2

Uncertain significance, flagged submission	clinical testing	Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	Jan 01, 2014	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Sep 06, 2016	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	May 07, 2018	The ADCK3 c.811C>T (p.Arg271Cys) missense variant has been reported in three studies in which it is found in at least four individuals with ataxia including in a homozygous state in one individual, in a compound heterozygous state in at least three individuals including two siblings (Horvath et al. 2012; Mignot et al. 2013; Bargiela et al. 2015). The p.Arg271Cys variant was absent from 100 healthy controls and is reported at a frequency of 0.00139 in the European (Finnish) population of the Exome Aggregation Consortium. The Arg271 residue is conserved across vertebrates. Based on the evidence, the p.Arg271Cys variant is classified as likely pathogenic for coenzyme Q10 deficiency, spinocerebellar ataxia type. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	Variant interpreted as Likely pathogenic and reported on 04-27-2018 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	May 24, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Centre for Inherited Metabolic Diseases, Karolinska University Hospital	Mar 20, 2024	- -

not provided

Pathogenic:3Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 21, 2021	The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant appears to segregate with disease in at least one family. Assessment of experimental evidence regarding the effect of this variant on protein function is inconclusive. The results of an in vitro E. coli expression model suggest that this variant has a damaging effect on protein stability and folding, however additional research is needed to confirm these findings (PMID: 32337771). Computational tools predict that this variant is damaging. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	May 03, 2023	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 271 of the COQ8A protein (p.Arg271Cys). For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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. ClinVar contains an entry for this variant (Variation ID: 296015). This missense change has been observed in individual(s) with clinical features of primary coenzyme Q10 deficiency (PMID: 22036850, 29915382, 30548255). 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. This variant is present in population databases (rs145034527, gnomAD 0.08%). -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 01, 2019	In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Missense variants in nearby residues reported in the Human Gene Mutation Database (Stenson et al., 2014); This variant is associated with the following publications: (PMID: 24164873, 22036850, 26640698, 26757139, 29482223, 29915382, 30548255, 32637629, 32337771) -
Uncertain significance, flagged submission	clinical testing	Eurofins Ntd Llc (ga)	Oct 05, 2016	- -

See cases

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Nov 14, 2019

ACMG classification criteria: PS4, PM2, PM3, PP3 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Pathogenic

0.28

BayesDel_noAF

Pathogenic

0.33

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.76

D;.;D

Eigen

Pathogenic

0.79

Eigen_PC

Uncertain

0.65

FATHMM_MKL

Uncertain

0.93

LIST_S2

Pathogenic

1.0

.;D;D

M_CAP

Pathogenic

0.58

MetaRNN

Pathogenic

0.87

D;D;D

MetaSVM

Pathogenic

0.86

MutationTaster

Benign

1.0

D;D;D;D;D;D;D

PrimateAI

Pathogenic

0.94

PROVEAN

Pathogenic

-7.2

D;D;D

REVEL

Pathogenic

0.79

Sift

Pathogenic

0.0

D;D;D

Sift4G

Pathogenic

0.0

D;D;D

Polyphen

1.0

D;.;D

Vest4

0.98

MVP

0.90

MPC

0.35

ClinPred

0.99

GERP RS

4.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.92

gMVP

0.92

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