Submissions for variant NM_020247.5(COQ8A):c.811C>T (p.Arg271Cys)

gnomAD frequency: 0.00004  dbSNP: rs145034527

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000416392	SCV000355248	likely pathogenic	Autosomal recessive ataxia due to ubiquinone deficiency	2018-05-07	criteria provided, single submitter	clinical testing	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.
GeneDx	RCV000493536	SCV000581788	pathogenic	not provided	2019-11-01	criteria provided, single submitter	clinical testing	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)
Genetic Services Laboratory, University of Chicago	RCV000416392	SCV000593039	likely pathogenic	Autosomal recessive ataxia due to ubiquinone deficiency	2016-09-06	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000493536	SCV001880606	likely pathogenic	not provided	2021-09-21	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 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.
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV002252090	SCV002523348	likely pathogenic	See cases	2019-11-14	criteria provided, single submitter	clinical testing	ACMG classification criteria: PS4, PM2, PM3, PP3
Labcorp Genetics (formerly Invitae), Labcorp	RCV000493536	SCV003524122	pathogenic	not provided	2023-05-03	criteria provided, single submitter	clinical testing	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). For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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) has been performed at Invitae 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. ClinVar contains an entry for this variant (Variation ID: 296015). This missense change has been observed in individual(s) with clinical features of primary coenzyme Q10 deficiency (PMID: 22036850, 29915382, 30548255). 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. This variant is present in population databases (rs145034527, gnomAD 0.08%).
Revvity Omics, Revvity	RCV000416392	SCV004238557	likely pathogenic	Autosomal recessive ataxia due to ubiquinone deficiency	2023-05-24	criteria provided, single submitter	clinical testing
Centre for Inherited Metabolic Diseases, Karolinska University Hospital	RCV000416392	SCV004801678	pathogenic	Autosomal recessive ataxia due to ubiquinone deficiency	2024-03-20	criteria provided, single submitter	clinical testing
GeneReviews	RCV000416392	SCV000494104	not provided	Autosomal recessive ataxia due to ubiquinone deficiency		no assertion provided	literature only
Eurofins Ntd Llc (ga)	RCV000493536	SCV000701080	uncertain significance	not provided	2016-10-05	flagged submission	clinical testing
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	RCV000416392	SCV000965805	uncertain significance	Autosomal recessive ataxia due to ubiquinone deficiency	2014-01-01	flagged submission	clinical testing
GenomeConnect, ClinGen	RCV000416392	SCV002074957	not provided	Autosomal recessive ataxia due to ubiquinone deficiency		no assertion provided	phenotyping only	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.