Submissions for variant NM_020247.5(COQ8A):c.911C>T (p.Ala304Val)

gnomAD frequency: 0.00002  dbSNP: rs748118737

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000427376	SCV000521310	likely pathogenic	not provided	2019-09-06	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: 29482223, 27106809, 22036850)
Illumina Laboratory Services, Illumina	RCV000778971	SCV000915399	uncertain significance	ADCK3-related disorder	2018-08-10	criteria provided, single submitter	clinical testing	The ADCK3 c.911C>T (p.Ala304Val) missense variant has been reported in two studies in which it is identified in a homozygous state in two unrelated individuals with cerebellar ataxia (Horvath et al. 2012; Mallaret et al. 2016). It was also described in an individual with coenzyme Q deficiency (Hughes et al. 2017). The p.Ala304Val variant was absent from 100 controls but is reported at a frequency of 0.000079 in the European (non-Finnish) population of the Genome Aggregation Database. Another missense variant at this position, p.Ala304Thr, has also been reported in affected individuals (Horvath et al. 2012). Multiple in silico tools predict a deleterious effect of the variant, but functional studies have not been conducted. The evidence for this variant is limited. Therefore, the p.Ala304Val variant is classified as of uncertain significance but suspicious for pathogenicity for ADCK3-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
CeGaT Center for Human Genetics Tuebingen	RCV000427376	SCV001335227	likely pathogenic	not provided	2023-04-01	criteria provided, single submitter	clinical testing	COQ8A: PM2, PM3, PM5, PP3
Molecular Genetics, Royal Melbourne Hospital	RCV001782903	SCV002503862	likely pathogenic	Autosomal recessive ataxia due to ubiquinone deficiency	2020-10-26	criteria provided, single submitter	clinical testing	This sequence change is predicted to replace alanine with valine at codon 304 of the COQ8A protein (p.Ala304Val). The alanine residue is highly conserved (100 vertebrates, UCSC), and is located in an alpha-helix. There is a small physicochemical difference between alanine and valine, but the substitution is predicted to cause a steric clash with Pro335 and Ala338 (PMID: 25498144). The variant is present in a large population cohort at a frequency of 0.004%, which is consistent with recessive conditions (rs748118737, 11/282,096 alleles, 0 homozygotes in gnomAD v2.1). It has been identified in the homozygous state in two unrelated individuals with cerebellar ataxia (PMID: 22036850, 27142713). In one of these individuals non-genetic biochemical tests in a muscle biopsy were conducted to confirm coenzyme Q10 deficiency, and showed combined respiratory chain deficiency and significantly decreased coenzyme Q10 (PMID: 22036850). Multiple lines of computational evidence predict a deleterious effect for the missense substitution (6/7 algorithms). Additionally, another missense substitution at this position (p.Ala304Thr) has been identified in an individual with cerebellar ataxia (PMID: 22036850). Based on the classification scheme RMH ACMG Guidelines v1.1.1, this variant is classified as LIKELY PATHOGENIC. Following criteria are met: PM2, PM3, PP3, PP4.
Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	RCV001782903	SCV002764975	likely pathogenic	Autosomal recessive ataxia due to ubiquinone deficiency	2020-08-17	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000427376	SCV002771177	uncertain significance	not provided	2022-09-26	criteria provided, single submitter	clinical testing	Available data are insufficient to determine the clinical significance of the variant at this time. The frequency of this variant in the general population is uninformative in assessment of its pathogenicity (http://gnomad.broadinstitute.org). This variant has been identified in multiple unrelated individuals with clinical features associated with this gene. Computational tools predict that this variant is damaging.
Invitae	RCV000427376	SCV003523502	likely pathogenic	not provided	2023-09-01	criteria provided, single submitter	clinical testing	In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Ala304 amino acid residue in COQ8A. Other variant(s) that disrupt this residue have been observed in individuals with COQ8A-related conditions (PMID: 22036850), which suggests that this may be a clinically significant amino acid residue. 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. ClinVar contains an entry for this variant (Variation ID: 381728). This missense change has been observed in individuals with clinical features of coenzyme Q10 deficiency (PMID: 22036850, 27142713, 29482223, 33949708). This variant is present in population databases (rs748118737, gnomAD 0.008%). This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 304 of the COQ8A protein (p.Ala304Val).