Submissions for variant NM_020247.5(COQ8A):c.812G>A (p.Arg271His)

gnomAD frequency: 0.00003  dbSNP: rs765859566

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV001197689	SCV001368468	uncertain significance	See cases	2019-01-09	criteria provided, single submitter	clinical testing	This variant was classified as: Uncertain significance. The available evidence favors the pathogenic nature of this variant, however the currently available data is insufficient to conclusively support its pathogenic nature. Thus this variant is classified as Uncertain significance - favor pathogenic. The following ACMG criteria were applied in classifying this variant: PM2,PP3.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002560240	SCV003500088	pathogenic	not provided	2024-01-31	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 271 of the COQ8A protein (p.Arg271His). This variant is present in population databases (rs765859566, gnomAD 0.004%). This missense change has been observed in individual(s) with clinical features of coenzyme Q10 deficiency (PMID: 34663476; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 931276). 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 with a positive predictive value of 80%. This variant disrupts the p.Arg271 amino acid residue in COQ8A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 22036850, 29915382, 30548255, 32337771). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.