rs143441644
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
Consequence
NM_016035.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
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COQ4 | NM_016035.5 | c.718C>T | p.Arg240Cys | missense_variant | Exon 7 of 7 | ENST00000300452.8 | NP_057119.3 | |
COQ4 | NM_001305942.2 | c.*94C>T | 3_prime_UTR_variant | Exon 4 of 4 | NP_001292871.2 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000164 AC: 25AN: 152062Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000198 AC: 49AN: 247440Hom.: 0 AF XY: 0.000202 AC XY: 27AN XY: 133980
GnomAD4 exome AF: 0.0000843 AC: 123AN: 1458250Hom.: 0 Cov.: 30 AF XY: 0.0000951 AC XY: 69AN XY: 725372
GnomAD4 genome AF: 0.000164 AC: 25AN: 152062Hom.: 0 Cov.: 32 AF XY: 0.000202 AC XY: 15AN XY: 74262
ClinVar
Submissions by phenotype
Neonatal encephalomyopathy-cardiomyopathy-respiratory distress syndrome Pathogenic:6Other:1
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. -
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not provided Pathogenic:2
PP3, PM2_moderate, PM3_strong, PS3, PS4_moderate -
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
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
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
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Neonatal encephalomyopathy-cardiomyopathy-respiratory distress syndrome;C5882738:Spastic ataxia 10, autosomal recessive Pathogenic:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at