Submissions for variant NM_020247.5(COQ8A):c.1844dup (p.Ser616fs)

dbSNP: rs764847439

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000195954	SCV000251075	pathogenic	not provided	2019-01-17	criteria provided, single submitter	clinical testing	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.
Athena Diagnostics Inc	RCV000195954	SCV000612251	pathogenic	not provided	2017-02-22	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000778224	SCV000914392	uncertain significance	ADCK3-Related Disorders	2018-10-30	criteria provided, single submitter	clinical testing	The ADCK3 c.1844dupG (p.Ser616LeufsTer114) variant results in a frameshift, and is predicted to cause an elongation of the protein. This variant is located in the last exon of the gene and may escape nonsense-mediated decay. The p.Ser616LeufsTer114 variant has been reported in one study in which it was identified in a homozygous state in two affected siblings with an adolescence onset of cerebellar ataxia and severe myoclonus from a consanguineous Pakistani family (Liu et al. 2014). Patient fibroblasts from the proband showed significantly reduced levels of coenzyme Q10 (CoQ10) and reduced activity of mitochondrial complex I and complexes IIΓÇôIII compared to controls. Furthermore, the symptoms of the proband improved upon treatment with CoQ10. Control data are unavailable for this variant, which is reported at a frequency of 0.0003180 in the East Asian population of the Genome Aggregation Database. Based on the limited evidence and potential impact of frameshift variants, the ADCK3 p.Ser616LeufsTer114 variant is classified as a variant of unknown significance but suspicious for pathogenicity for an autosomal recessive form of spinocerebellar ataxia associated with primary coenzyme Q10 deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Invitae	RCV000195954	SCV002134137	pathogenic	not provided	2022-07-06	criteria provided, single submitter	clinical testing	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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000416393	SCV004122573	pathogenic	Autosomal recessive ataxia due to ubiquinone deficiency	2023-10-06	criteria provided, single submitter	clinical testing	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.
GeneReviews	RCV000416393	SCV000494107	not provided	Autosomal recessive ataxia due to ubiquinone deficiency		no assertion provided	literature only