Submissions for variant NM_020247.5(COQ8A):c.730G>C (p.Gly244Arg)

gnomAD frequency: 0.00048  dbSNP: rs199619932

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001803792	SCV000602437	uncertain significance	Autosomal recessive ataxia due to ubiquinone deficiency	2021-08-20	criteria provided, single submitter	clinical testing	The p.Gly244Arg variant (rs199619932) has not been reported in the medical literature, is not listed in gene-specific variant databases, nor has it been previously identified in our laboratory. It is listed in the Genome Aggregation Database (gnomAD) browser with a frequency in non-Finnish European populations of 0.086% (identified in 62 out of 72,122 chromosomes). The glycine at codon 244 is highly conserved considering 13 species up to C. elegans (Alamut software v2.9), although computational analyses return mixed results regarding the effect of this variant on COQ8A protein structure/function (SIFT: tolerated, PolyPhen2: benign, and Mutation Taster: disease causing). Additionally, this variant affects the last nucleotide of exon 5, and is computationally predicted to alter splicing at this junction (Alamut software v2.9). However, in the absence of mRNA studies, such predictions are not sufficient to assign pathogenicity. Therefore, based on the available information, the clinical significance of the p.Gly244Arg variant cannot be determined with certainty.
Athena Diagnostics	RCV000710481	SCV000840711	uncertain significance	not provided	2023-08-29	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 higher than would generally be expected for pathogenic variants in this gene. (http://gnomad.broadinstitute.org) Computational tools yielded predictions that this variant may interfere with normal RNA splicing.
Genetic Services Laboratory, University of Chicago	RCV001814985	SCV002061965	uncertain significance	not specified	2017-09-27	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000710481	SCV002062881	uncertain significance	not provided	2021-12-01	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000710481	SCV002191374	uncertain significance	not provided	2022-10-25	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 244 of the COQ8A protein (p.Gly244Arg). This variant also falls at the last nucleotide of exon 5, which is part of the consensus splice site for this exon. This variant is present in population databases (rs199619932, gnomAD 0.09%). This variant has not been reported in the literature in individuals affected with COQ8A-related conditions. ClinVar contains an entry for this variant (Variation ID: 439390). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics	RCV002527344	SCV003654008	uncertain significance	Inborn genetic diseases	2022-01-21	criteria provided, single submitter	clinical testing	The c.730G>C (p.G244R) alteration is located in exon 5 (coding exon 4) of the COQ8A gene. This alteration results from a G to C substitution at nucleotide position 730, causing the glycine (G) at amino acid position 244 to be replaced by an arginine (R). Based on data from gnomAD, the C allele has an overall frequency of 0.04% (80/189108) total alleles studied. The highest observed frequency was 0.09% (68/75612) of European (non-Finnish) alleles. This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis for this alteration is inconclusive. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.