rs1057519344

Variant names:

• chr1-226983549-C-CAGT
• rs1057519344
• NM_020247.5:c.1081-1_1082dupGTA

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_020247.5(COQ8A):​c.1081-1_1082dupGTA​(p.Gln360_Tyr361insTer) variant causes a stop gained, disruptive inframe insertion, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000411 in 1,461,396 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: COQ8A NM_020247.5 stop_gained, disruptive_inframe_insertion, splice_region
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1 O:1
• Conservation: PhyloP100: 9.24
• Publications: 1 publications found

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]

COQ8A Gene-Disease associations (from GenCC):

• autosomal recessive ataxia due to ubiquinone deficiency

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, G2P
• coenzyme Q10 deficiency

  Inheritance: AR Classification: DEFINITIVE Submitted by: Illumina

ENSG00000288674 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 11 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 1-226983549-C-CAGT is Pathogenic according to our data. Variant chr1-226983549-C-CAGT is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 375333.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COQ8A	NM_020247.5	c.1081-1_1082dupGTA	p.Gln360_Tyr361insTer	stop_gained, disruptive_inframe_insertion, splice_region_variant	Exon 9 of 15	ENST00000366777.4	NP_064632.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COQ8A	ENST00000366777.4	c.1081-1_1082dupGTA	p.Gln360_Tyr361insTer	stop_gained, disruptive_inframe_insertion, splice_region_variant	Exon 9 of 15	1	NM_020247.5	ENSP00000355739.3
ENSG00000288674	ENST00000366779.6	n.*5808-1_*5809dupGTA		splice_region_variant, non_coding_transcript_exon_variant	Exon 26 of 32	2		ENSP00000355741.2
ENSG00000288674	ENST00000366779.6	n.*5808-1_*5809dupGTA		3_prime_UTR_variant	Exon 26 of 32	2		ENSP00000355741.2

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.00000411 AC: 6 AN: 1461396 Hom.: 0 Cov.: 33 AF XY: 0.00000550 AC XY: 4 AN XY: 727030

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.0000224 AC: 1 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53070

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1111872

Other (OTH) AF: 0.0000166 AC: 1 AN: 60392

GnomAD4 genome Cov.: 34

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Autosomal recessive ataxia due to ubiquinone deficiency Pathogenic:1 Other:1

Mar 28, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: CABC1 (COQ8A) c.1081-1_1082dupGTA is located in a canonical splice-site. The frequency of this variant in the general population could not be determined (not present in gnomAD). c.1081-1_1082dupGTA, reported to create an in-frame stop codon (p.Gln360_Tyr361ins*), has been documented in the literature in individuals affected with Autosomal Recessive Ataxia Due To Ubiquinone Deficiency (Mignot_2013, Traschutz_2020). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic. -

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GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

not provided Uncertain:1

May 25, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change falls in intron 9 of the COQ8A gene. It does not directly change the encoded amino acid sequence of the COQ8A protein. It affects a nucleotide within the consensus splice site. 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. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. ClinVar contains an entry for this variant (Variation ID: 375333). This variant is also known as p.Gln360_Tyr361ins*. This variant has been observed in individual(s) with clinical features of COQ8A-related conditions (PMID: 24164873). This variant is not present in population databases (gnomAD no frequency). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		9.2
Mutation Taster		=4/96	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs1057519344; hg19: chr1-227171250;