rs143441644

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1PM2PP5_Very_Strong

The NM_016035.5(COQ4):c.718C>T(p.Arg240Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000919 in 1,610,312 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.00016 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000084 ( 0 hom. )

Consequence

COQ4
NM_016035.5 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:12O:1

Conservation

PhyloP100: 5.56

Variant links:

Genes affected

COQ4 (HGNC:19693): (coenzyme Q4) This gene encodes a component of the coenzyme Q biosynthesis pathway. Coenzyme Q, an essential component of the electron transport chain, shuttles electrons between complexes I or II to complex III of the mitochondrial transport chain. This protein appears to play a structural role in stabilizing a complex that contains most of the coenzyme Q biosynthesis enzymes. Mutations in this gene are associated with mitochondrial disorders linked to coenzyme Q deficiency. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Apr 2015]

COQ4 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PM1

In a chain Ubiquinone biosynthesis protein COQ4 homolog, mitochondrial (size 234) in uniprot entity COQ4_HUMAN there are 27 pathogenic changes around while only 3 benign (90%) in NM_016035.5

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 9-128333565-C-T is Pathogenic according to our data. Variant chr9-128333565-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 189201.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-128333565-C-T is described in Lovd as [Pathogenic]. Variant chr9-128333565-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COQ4	NM_016035.5 link	c.718C>T	p.Arg240Cys	missense_variant	Exon 7 of 7	ENST00000300452.8	NP_057119.3	Q9Y3A0-1
COQ4	NM_001305942.2 link	c.*94C>T		3_prime_UTR_variant	Exon 4 of 4		NP_001292871.2	A0A024R890

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COQ4	ENST00000300452.8 link	c.718C>T	p.Arg240Cys	missense_variant	Exon 7 of 7	1	NM_016035.5	ENSP00000300452.3		Q9Y3A0-1
COQ4	ENST00000461102.1 link	n.2624C>T		non_coding_transcript_exon_variant	Exon 2 of 2	2

Frequencies

GnomAD3 genomes

AF:

0.000164

AC:

AN:

152062

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00490

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:

0.000958

GnomAD3 exomes

AF:

0.000198

AC:

AN:

247440

Hom.:

AF XY:

0.000202

AC XY:

AN XY:

133980

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000294

Gnomad ASJ exome

AF:

0.00352

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000804

Gnomad OTH exome

AF:

0.000668

GnomAD4 exome

AF:

0.0000843

AC:

123

AN:

1458250

Hom.:

Cov.:

AF XY:

0.0000951

AC XY:

AN XY:

725372

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000902

Gnomad4 ASJ exome

AF:

0.00269

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000117

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000288

Gnomad4 OTH exome

AF:

0.000266

GnomAD4 genome

AF:

0.000164

AC:

AN:

152062

Hom.:

Cov.:

AF XY:

0.000202

AC XY:

AN XY:

74262

show subpopulations

Gnomad4 AFR

AF:

0.0000242

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00490

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.000958

Alfa

AF:

0.000228

Hom.:

Bravo

AF:

0.000166

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.000239

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:12Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Neonatal encephalomyopathy-cardiomyopathy-respiratory distress syndrome

Pathogenic:6Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 16, 2024	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). 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) has been performed 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. -
not provided, no classification provided	literature only	GeneReviews	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	New York Genome Center	Aug 27, 2021	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 05, 2015	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jun 02, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Sep 02, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	Oct 19, 2017	- -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jan 09, 2024	PP3, PM2_moderate, PM3_strong, PS3, PS4_moderate -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 10, 2022	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) -

Inborn genetic diseases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

May 05, 2022

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. -

COQ4-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 16, 2024

The COQ4 c.718C>T variant is predicted to result in the amino acid substitution p.Arg240Cys. This variant has been reported in the homozygous and compound heterozygous states in multiple 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). Functional characterization suggests that this variant has a deleterious effect on the protein (Brea-Calvo et al. 2015. PubMed ID: 25658047). This variant is reported in 0.34% of alleles in individuals of Ashkenazi Jewish descent in gnomAD. This variant is interpreted as pathogenic. -

Spastic ataxia

Pathogenic:1

Pathogenic, criteria provided, single submitter

research

Molecular Medicine for Neurodegenerative and Neuromuscular Diseases Unit, IRCCS Fondazione Stella Maris

Jan 04, 2021

- -

Neonatal encephalomyopathy-cardiomyopathy-respiratory distress syndrome;C5882738:Spastic ataxia 10, autosomal recessive

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 15, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.30

BayesDel_addAF

Uncertain

0.15

BayesDel_noAF

Pathogenic

0.17

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.58

Eigen

Pathogenic

0.78

Eigen_PC

Pathogenic

0.75

FATHMM_MKL

Uncertain

0.96

LIST_S2

Pathogenic

0.97

M_CAP

Uncertain

0.22

MetaRNN

Uncertain

0.49

MetaSVM

Benign

-0.59

MutationAssessor

Uncertain

2.6

PrimateAI

Uncertain

0.54

PROVEAN

Pathogenic

-6.7

REVEL

Pathogenic

0.79

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.015

Polyphen

1.0

Vest4

0.94

MVP

0.69

MPC

1.4

ClinPred

0.90

GERP RS

5.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.86

gMVP

0.79

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