1-226985332-G-C

Variant names:

• chr1-226985332-G-C
• rs119468004
• NM_020247.5:c.1651G>C

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM2 PM5 PP3_Moderate PP5_Moderate

The NM_020247.5(COQ8A):​c.1651G>C​(p.Glu551Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E551K) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: COQ8A NM_020247.5 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 9.99

Genes affected

COQ8A (HGNC:16812): (coenzyme Q8A) This gene encodes a mitochondrial protein similar to yeast ABC1, which functions in an electron-transferring membrane protein complex in the respiratory chain. It is not related to the family of ABC transporter proteins. Expression of this gene is induced by the tumor suppressor p53 and in response to DNA damage, and inhibiting its expression partially suppresses p53-induced apoptosis. Alternatively spliced transcript variants have been found; however, their full-length nature has not been determined. [provided by RefSeq, Jul 2008]

ENSG00000288674 (HGNC:):

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-226985332-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 3636.We mark this variant Likely_pathogenic, oryginal submissions are: {not_provided=1, Likely_pathogenic=5, Uncertain_significance=1, Pathogenic=1}.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.858
• PP5: Variant 1-226985332-G-C is Pathogenic according to our data. Variant chr1-226985332-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3666430.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COQ8A	NM_020247.5	c.1651G>C	p.Glu551Gln	missense_variant	Exon 14 of 15	ENST00000366777.4	NP_064632.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COQ8A	ENST00000366777.4	c.1651G>C	p.Glu551Gln	missense_variant	Exon 14 of 15	1	NM_020247.5	ENSP00000355739.3
ENSG00000288674	ENST00000366779.6	n.*6378G>C		non_coding_transcript_exon_variant	Exon 31 of 32	2		ENSP00000355741.2
ENSG00000288674	ENST00000366779.6	n.*6378G>C		3_prime_UTR_variant	Exon 31 of 32	2		ENSP00000355741.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Oct 21, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glutamic acid, which is acidic and polar, with glutamine, which is neutral and polar, at codon 551 of the COQ8A protein (p.Glu551Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of COQ8A-related conditions (internal data). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt COQ8A protein function with a positive predictive value of 80%. This variant disrupts the p.Glu551 amino acid residue in COQ8A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 18319072, 29915382). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.37
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.58	D;.;D
Eigen	Pathogenic	0.97
Eigen_PC	Pathogenic	0.88
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	1.0	.;D;D
M_CAP	Uncertain	0.093	D
MetaRNN	Pathogenic	0.86	D;D;D
MetaSVM	Uncertain	0.67	D
PrimateAI	Uncertain	0.67	T
PROVEAN	Uncertain	-2.9	D;D;D
REVEL	Uncertain	0.59
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;.;D
Vest4		0.89
MutPred		0.49		Gain of methylation at K553 (P = 0.0973);.;Gain of methylation at K553 (P = 0.0973);
MVP		0.95
MPC		0.31
ClinPred		1.0	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.86
gMVP		0.88
Mutation Taster		=9/91	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs119468004; hg19: chr1-227173033;