rs143441644

chr9-128333565-C-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1 PM2 PM5 PP5_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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R240H) has been classified as Pathogenic.

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000084 (0 hom.)
• Consequence: COQ4 NM_016035.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:11 O:1
• Conservation: PhyloP100: 5.56

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]

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PM1: In a chain Ubiquinone biosynthesis protein COQ4 homolog, mitochondrial (size 234) in uniprot entity COQ4_HUMAN there are 48 pathogenic changes around while only 10 benign (83%) in NM_016035.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr9-128333566-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 2686021.Status of the report is no_assertion_criteria_provided, 0 stars.
• 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/exons	MANE	UniProt
COQ4	NM_016035.5	c.718C>T	p.Arg240Cys	missense_variant	7/7	ENST00000300452.8
COQ4	NM_001305942.2	c.*94C>T		3_prime_UTR_variant	4/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COQ4	ENST00000300452.8	c.718C>T	p.Arg240Cys	missense_variant	7/7	1	NM_016035.5	P1
COQ4	ENST00000461102.1	n.2624C>T		non_coding_transcript_exon_variant	2/2	2

Frequencies

GnomAD3 genomes AF: 0.000164 AC: 25 AN: 152062 Hom.: 0 Cov.: 32

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: 49 AN: 247440 Hom.: 0 AF XY: 0.000202 AC XY: 27 AN XY: 133980

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.: 0 Cov.: 30 AF XY: 0.0000951 AC XY: 69 AN XY: 725372

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: 25 AN: 152062 Hom.: 0 Cov.: 32 AF XY: 0.000202 AC XY: 15 AN XY: 74262

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.: 0

Bravo AF: 0.000166

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.000239 AC: 29

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:11 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Neonatal encephalomyopathy-cardiomyopathy-respiratory distress syndrome Pathogenic:6 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	Oct 19, 2017	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jun 02, 2023	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	New York Genome Center	Aug 27, 2021	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 18, 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). 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 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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Sep 28, 2021	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 05, 2015	- -

not provided Pathogenic:2

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) -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Mar 29, 2023	PP3, PM2_strong, PM3_strong, PS3, PS4_moderate -

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, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 08, 2023

The COQ4 c.718C>T variant is predicted to result in the amino acid substitution p.Arg240Cys. This variant was found in the homozygous and compound heterozygous state in multiple affected 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). This variant is reported in 0.34% of alleles in individuals of Ashkenazi Jewish descent in gnomAD (http://gnomad.broadinstitute.org/variant/9-131095844-C-T). Functional characterization suggests that this variant has a deleterious effect on the protein (Brea-Calvo et al. 2015. PubMed ID: 25658047). 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

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Pathogenic	0.17
Cadd	Pathogenic	30
Dann	Pathogenic	1.0
DEOGEN2	Uncertain	0.58	D
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.97	D
M_CAP	Uncertain	0.22	D
MetaRNN	Uncertain	0.49	T
MetaSVM	Benign	-0.59	T
MutationAssessor	Uncertain	2.6	M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.54	T
PROVEAN	Pathogenic	-6.7	D
REVEL	Pathogenic	0.79
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.015	D
Polyphen		1.0	D
Vest4		0.94
MVP		0.69
MPC		1.4
ClinPred		0.90	D
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

Other links and lift over

dbSNP: rs143441644; hg19: chr9-131095844;