1-226982107-C-T
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PM5PP3_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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R271H) has been classified as Likely pathogenic.
Frequency
Consequence
NM_020247.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
COQ8A | ENST00000366777.4 | c.811C>T | p.Arg271Cys | missense_variant | Exon 6 of 15 | 1 | NM_020247.5 | ENSP00000355739.3 | ||
ENSG00000288674 | ENST00000366779.6 | n.*5538C>T | non_coding_transcript_exon_variant | Exon 23 of 32 | 2 | ENSP00000355741.2 | ||||
ENSG00000288674 | ENST00000366779.6 | n.*5538C>T | 3_prime_UTR_variant | Exon 23 of 32 | 2 | ENSP00000355741.2 |
Frequencies
GnomAD3 genomes AF: 0.0000460 AC: 7AN: 152154Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000103 AC: 25AN: 241910Hom.: 0 AF XY: 0.000122 AC XY: 16AN XY: 131670
GnomAD4 exome AF: 0.0000446 AC: 65AN: 1457560Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 39AN XY: 724816
GnomAD4 genome AF: 0.0000460 AC: 7AN: 152154Hom.: 0 Cov.: 33 AF XY: 0.0000404 AC XY: 3AN XY: 74316
ClinVar
Submissions by phenotype
Autosomal recessive ataxia due to ubiquinone deficiency Pathogenic:4Uncertain:1Other:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | May 24, 2023 | - - |
Uncertain significance, flagged submission | clinical testing | Equipe Genetique des Anomalies du Developpement, Université de Bourgogne | Jan 01, 2014 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Centre for Inherited Metabolic Diseases, Karolinska University Hospital | Mar 20, 2024 | - - |
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. - |
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 | - - |
not provided Pathogenic:4Uncertain:1
Uncertain significance, flagged submission | clinical testing | Eurofins Ntd Llc (ga) | Oct 05, 2016 | - - |
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) - |
Pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Aug 28, 2024 | PP1_strong, PP3, PM2, PM3, PS4_moderate - |
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Nov 28, 2024 | 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). This variant is present in population databases (rs145034527, gnomAD 0.08%). This missense change has been observed in individual(s) with clinical features of primary coenzyme Q10 deficiency (PMID: 22036850, 29915382, 30548255, 32337771). 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: 296015). 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 COQ8A protein function. Experimental studies have shown that this missense change affects COQ8A function (PMID: 32337771). For these reasons, this variant has been classified as Pathogenic. - |
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. - |
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:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at