chr1-226982719-C-T
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong
The NM_020247.5(COQ8A):c.895C>T(p.Arg299Trp) variant causes a missense change. The variant allele was found at a frequency of 0.0000297 in 1,613,560 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
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.895C>T | p.Arg299Trp | missense_variant | Exon 7 of 15 | 1 | NM_020247.5 | ENSP00000355739.3 | ||
ENSG00000288674 | ENST00000366779.6 | n.*5622C>T | non_coding_transcript_exon_variant | Exon 24 of 32 | 2 | ENSP00000355741.2 | ||||
ENSG00000288674 | ENST00000366779.6 | n.*5622C>T | 3_prime_UTR_variant | Exon 24 of 32 | 2 | ENSP00000355741.2 |
Frequencies
GnomAD3 genomes AF: 0.0000263 AC: 4AN: 152186Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000279 AC: 7AN: 250868Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135792
GnomAD4 exome AF: 0.0000301 AC: 44AN: 1461374Hom.: 0 Cov.: 33 AF XY: 0.0000261 AC XY: 19AN XY: 726988
GnomAD4 genome AF: 0.0000263 AC: 4AN: 152186Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74346
ClinVar
Submissions by phenotype
Autosomal recessive ataxia due to ubiquinone deficiency Pathogenic:4Other:1
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.003%). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.78; 3Cnet: 0.94). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000372655). The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 22036850, 24164873, 27106809, 27142713, 30637285, 32337771). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least 2 similarly affected unrelated individuals (PMID: 22036850, 24164873, 27106809, 27142713). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -
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This sequence change in COQ8A is predicted to replace arginine with tryptophan at codon 299, p.(Arg299Trp). The arginine residue is highly conserved (100 vertebrates, UCSC), and is located in a helical region. There is a large physicochemical difference between arginine and tryptophan. The highest population minor allele frequency in gnomAD v2.1 is 0.006% (2/34,578 alleles) in the Latino/admixed American population, which is consistent with a recessive condition. This variant has been detected in at least six individuals with ataxia due to coenzyme Q10 deficiency. Of those individuals, two individuals were homozygous and three were compound heterozygous for the variant and a pathogenic or likely pathogenic variant and two of those were confirmed in trans by parental/family testing (PMID: 22036850, 24164873, 27106809, 27142713). The variant has been reported to segregate with disease in at least two families (PMID: 24164873, 27106809). Multiple lines of computational evidence predict a deleterious effect for the missense substitution (4/5 algorithms). Based on the classification scheme RMH Modified ACMG Guidelines v1.5.1, this variant is classified as PATHOGENIC. Following criteria are met: PM3_VeryStrong, PP1_Moderate, PM2_Supporting, PP3. -
not provided Pathogenic:3
The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been identified in at least one individual with clinical features associated with this gene. In multiple individuals, this variant has been seen with a single recessive pathogenic variant in the same gene, suggesting this variant may also be pathogenic. Computational tools predict that this variant is damaging. -
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 299 of the COQ8A protein (p.Arg299Trp). This variant is present in population databases (rs201908721, gnomAD 0.009%). This missense change has been observed in individuals with clinical features of coenzyme Q10 deficiency (PMID: 22036850, 32337771). ClinVar contains an entry for this variant (Variation ID: 372655). 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) performed at Invitae indicates that this missense variant is expected to disrupt COQ8A protein function. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. For these reasons, this variant has been classified as Pathogenic. -
In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 33057194, 37090936, 35982159, 27106809, 22036850, 24164873, 27142713, 30637285, 32337771, 34638552, 30968303) -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at