Submissions for variant NM_020247.5(COQ8A):c.895C>T (p.Arg299Trp)

gnomAD frequency: 0.00003  dbSNP: rs201908721

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000413531	SCV000491037	pathogenic	not provided	2019-11-04	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 22036850, 27106809, 24164873, 27142713, 30637285, 32337771)
Athena Diagnostics	RCV000413531	SCV001142960	likely pathogenic	not provided	2020-11-20	criteria provided, single submitter	clinical testing	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.
Invitae	RCV000413531	SCV002183911	pathogenic	not provided	2021-12-28	criteria provided, single submitter	clinical testing	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.
Mendelics	RCV000416388	SCV002519429	pathogenic	Autosomal recessive ataxia due to ubiquinone deficiency	2022-05-04	criteria provided, single submitter	clinical testing
3billion	RCV000416388	SCV003841356	pathogenic	Autosomal recessive ataxia due to ubiquinone deficiency	2023-02-23	criteria provided, single submitter	clinical testing	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.
Neuberg Centre For Genomic Medicine, NCGM	RCV000416388	SCV004176464	pathogenic	Autosomal recessive ataxia due to ubiquinone deficiency	2023-03-01	criteria provided, single submitter	clinical testing
Molecular Genetics, Royal Melbourne Hospital	RCV000416388	SCV004812570	pathogenic	Autosomal recessive ataxia due to ubiquinone deficiency	2022-07-01	criteria provided, single submitter	clinical testing	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.
GeneReviews	RCV000416388	SCV000494101	not provided	Autosomal recessive ataxia due to ubiquinone deficiency		no assertion provided	literature only