rs1556423388

Variant names:

• chrM-8086-AT-A
• rs1556423388
• ENST00000361739.1:c.503delT

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PVS1_Strong PS3_Supporting PM6 PP4 PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The m.8088delT frameshift variant in MT-CO2 has been reported in one individual with primary mitochondrial disease to date, in a 16-year-old girl with childhood onset exercise intolerance, fatigue, and muscle weakness (PMID:30315213). Muscle biopsy showed COX deficiency, subsarcolemmal accumulation of mitochondria, and lipid accumulation. Complex IV activity was reduced in muscle (exome sequencing was performed excluding other genetic etiologies, PP4). The variant was present at 96% heteroplasmy in skeletal muscle, 2% in hair follicles, 5% in blood, 6% in fibroblasts, 12% in buccal sample, and 15% in urine. The variant was not detected in her mother’s hair follicles, blood, buccal sample, or urine (PM6; PMID:30315213). This variant causes a premature stop in the MT-CO2 gene resulting in truncation of 26% of the protein (PVS1_strong). This variant is absent in the MITOMAP GenBank dataset, gnomAD v3.1.2, and the Helix dataset (PM2_supporting). There are no in silico predictors for this type of variant in mitochondrial DNA. Single fiber testing showed higher levels of the variant in COX negative fibers (100%, n=14) than in COX positive fibers (40%, n=14), p<0.05 (PS3_supporting, PMID:30315213). In summary, this variant meets criteria to be classified as likely pathogenic for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on February 26, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID:32906214): PVS1_strong, PP4, PM6, PM2_supporting, PS3_supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA658824402/MONDO:0044970/015

• Frequency: Mitomap GenBank: Absent
• Consequence: MT-CO2 ENST00000361739.1 frameshift
• Clinical Significance: Likely pathogenic reviewed by expert panel P:2 Mitochondrial-myopathy-with-complex-IV-deficiency
• Conservation: PhyloP100: -1.67
• Publications: 0 publications found

Genes affected

MT-CO2 (HGNC:7421): (mitochondrially encoded cytochrome c oxidase II) Contributes to cytochrome-c oxidase activity. Predicted to be involved in mitochondrial electron transport, cytochrome c to oxygen and positive regulation of vasoconstriction. Located in mitochondrial inner membrane. Part of respiratory chain complex IV. Biomarker of Huntington's disease and stomach cancer. [provided by Alliance of Genome Resources, Apr 2022]

TRNK (HGNC:7489): (mitochondrially encoded tRNA lysine)

TRNK Gene-Disease associations (from GenCC):

• Leigh syndrome

  Inheritance: Mitochondrial Classification: DEFINITIVE Submitted by: ClinGen
• mitochondrial disease

  Inheritance: Mitochondrial Classification: DEFINITIVE Submitted by: ClinGen
• maternally-inherited cardiomyopathy and hearing loss

  Inheritance: Mitochondrial Classification: SUPPORTIVE Submitted by: Orphanet
• MERRF syndrome

  Inheritance: Mitochondrial Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

• PVS1: For more information check the summary or visit ClinGen Evidence Repository.
• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM6: For more information check the summary or visit ClinGen Evidence Repository.
• PP4: For more information check the summary or visit ClinGen Evidence Repository.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000361739.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
There are no transcript annotations for this variant.

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MT-CO2	ENST00000361739.1	TSL:6	c.503delT	p.Leu168fs	frameshift	Exon 1 of 1	ENSP00000354876.1
	MT-TK	ENST00000387421.1	TSL:6	n.-208delT		upstream_gene	N/A

Frequencies

Mitomap GenBank The variant is not present, suggesting it is rare .

Mitomap

Disease(s): Mitochondrial-myopathy-with-complex-IV-deficiency

Status: Reported

ClinVar

ClinVar submissions as Germline

Significance: Likely pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
1	-	-	Mitochondrial complex IV deficiency, nuclear type 1 (1)
1	-	-	Mitochondrial disease (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-1.7

Other links and lift over

dbSNP: rs1556423388; hg19: chrM-8087;