1-226986631-TGGG-TGGGG
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Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_ModeratePM2PP5_Very_Strong
The NM_020247.5(COQ8A):c.1844dupG(p.Ser616fs) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000229 in 1,613,580 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Genomes: 𝑓 0.000046 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000021 ( 0 hom. )
Consequence
COQ8A
NM_020247.5 frameshift
NM_020247.5 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 9.99
Genes affected
COQ8A (HGNC:16812): (coenzyme Q8A) This gene encodes a mitochondrial protein similar to yeast ABC1, which functions in an electron-transferring membrane protein complex in the respiratory chain. It is not related to the family of ABC transporter proteins. Expression of this gene is induced by the tumor suppressor p53 and in response to DNA damage, and inhibiting its expression partially suppresses p53-induced apoptosis. Alternatively spliced transcript variants have been found; however, their full-length nature has not been determined. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 12 ACMG points.
PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0509 CDS is truncated, and there are 2 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 1-226986631-T-TG is Pathogenic according to our data. Variant chr1-226986631-T-TG is described in ClinVar as [Pathogenic]. Clinvar id is 214046.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| COQ8A | ENST00000366777.4 | c.1844dupG | p.Ser616fs | frameshift_variant | 15/15 | 1 | NM_020247.5 | ENSP00000355739.3 | ||
| ENSG00000288674 | ENST00000366779.6 | n.*6571dupG | non_coding_transcript_exon_variant | 32/32 | 2 | ENSP00000355741.2 | ||||
| ENSG00000288674 | ENST00000366779.6 | n.*6571dupG | 3_prime_UTR_variant | 32/32 | 2 | ENSP00000355741.2 |
Frequencies
GnomAD3 genomes 0.0000528 AC: 8AN: 151608Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000716 AC: 18AN: 251434Hom.: 0 AF XY: 0.0000515 AC XY: 7AN XY: 135904
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GnomAD4 exome AF: 0.0000205 AC: 30AN: 1461850Hom.: 0 Cov.: 33 AF XY: 0.0000206 AC XY: 15AN XY: 727220
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GnomAD4 genome 0.0000461 AC: 7AN: 151730Hom.: 0 Cov.: 32 AF XY: 0.0000540 AC XY: 4AN XY: 74094
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:5Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:3
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jan 17, 2019 | The c.1844dupG variant in the ADCK3 gene causes a frameshift starting with codon Serine 616, changes this amino acid to a Leucine residue and creates a premature Stop codon at position 114 of the new reading frame, denoted p.Ser616LeufsX114. This mutation is predicted to cause loss of normal protein function by resulting in the replacement of the last 32 amino acids of the ADCK3 protein by 113 incorrect amino acids, which is predicted to affect the secondary structure and function of the ADCK3 protein. Although this variant has not been previously reported to our knowledge, it is expected to be a pathogenic variant. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics | Feb 22, 2017 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jul 06, 2022 | This sequence change creates a premature translational stop signal (p.Ser616Leufs*114) in the COQ8A gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 32 amino acid(s) of the COQ8A protein. This variant is present in population databases (rs761498232, gnomAD 0.03%). This premature translational stop signal has been observed in individuals with clinical features of coenzyme Q10 deficiency (PMID: 24218524, 32743982, 32961396, 34663476). ClinVar contains an entry for this variant (Variation ID: 214046). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects COQ8A function (PMID: 24218524). This variant disrupts a region of the COQ8A protein in which other variant(s) (p.Arg626His) have been observed in individuals with COQ8A-related conditions (Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. - |
Autosomal recessive ataxia due to ubiquinone deficiency Pathogenic:2Other:1
| not provided, no classification provided | literature only | GeneReviews | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Oct 06, 2023 | Variant summary: CABC1 c.1844dupG (p.Ser616LeufsX114), located within the last exon, causes a frameshift which disrupts the last 32 amino acids of the encoded protein sequence and results in an extension of the protein, but is not predicted to undergo nonsense mediated decay. The variant allele was found at a frequency of 6.7e-05 in 282792 control chromosomes (gnomAD). c.1844dupG has been reported in the literature as a biallelic genotype in multiple individuals affected with Autosomal Recessive Ataxia Due To Ubiquinone Deficiency, including reports where symptoms have improved following CoQ10 supplementation, and has been found to segregate with the disease phenotype in at least one family (e.g. Liu_2014, Jiao_2020, Zhang_2020). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 32961396, 24218524, 32743982). Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Three submitters classified the variant as pathogenic, and one classified it as uncertain significance. Based on the evidence outlined above, the variant was classified as pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Sep 05, 2024 | - - |
Computational scores
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at