rs606231139

chr1-226965321-CAATCCCCTGTTGGGGGCCTCAC-CTTG

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_020247.5(COQ8A):c.500_521delinsTTG(p.Gln167LeufsTer36) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: COQ8A NM_020247.5 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 6.02

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]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-226965322-AATCCCCTGTTGGGGGCCTCAC-TTG is Pathogenic according to our data. Variant chr1-226965322-AATCCCCTGTTGGGGGCCTCAC-TTG is described in ClinVar as [Pathogenic]. Clinvar id is 3642.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COQ8A	NM_020247.5	c.500_521delinsTTG	p.Gln167LeufsTer36	frameshift_variant	3/15	ENST00000366777.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COQ8A	ENST00000366777.4	c.500_521delinsTTG	p.Gln167LeufsTer36	frameshift_variant	3/15	1	NM_020247.5	P1
COQ8A	ENST00000366778.5	c.344_365delinsTTG	p.Gln115LeufsTer36	frameshift_variant	3/15	1
COQ8A	ENST00000489044.1	n.711_732delinsTTG		non_coding_transcript_exon_variant	3/5	3
COQ8A	ENST00000478406.5	n.107-12127_107-12106delinsTTG		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes Cov.: 33

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Autosomal recessive ataxia due to ubiquinone deficiency Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Oct 01, 2010

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Nov 20, 2017

The c.500_521del22insTTG variant in the COQ8A gene has been reported previously as c.500_521delinsTTG in the homozygous state in an individual with childhood-onset cerebellar ataxia and cerebellar atrophy and was shown to result in decreased CoQ10 in fibroblasts, impaired cell growth, and decreased ATP production (Lagier-Tourenne et al., 2008; Quinzii et al., 2010). The c.500_521del22insTTG variant causes a frameshift starting with codon Glutamine 167, changes this amino acid to a Leucine residue, and creates a premature Stop codon at position 36 of the new reading frame, denoted p.Gln167LeufsX36. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The c.500_521del22insTTG variant is not observed in large population cohorts (Lek et al., 2016). We interpret c.500_521del22insTTG as a pathogenic variant. -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs606231139; hg19: chr1-227153023;