rs199474828

Variant names:

• chrM-8041-AAT-A
• rs199474828
• ENST00000361739.1:c.458_459delTA

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PVS1_Strong PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The m.8043_8044del frameshift variant in MT-CO2 has been reported in one individual with primary mitochondrial disease to date, in an infant with severe lactic acidosis who died at 12 days old (PMID:11471180). Complex IV deficiency was noted in skeletal and cardiac muscle. The variant was present at 20% heteroplasmy in skeletal muscle, 17% in cardiac muscle, 14% in lung tissue, 14% in liver, and 11.5% in skin. The variant was not assessed in proband’s blood and was undetectable in mother’s blood. Of note, nuclear genetic etiologies were not evaluated in this case. This variant causes a premature stop in the MT-CO2 gene resulting in truncation of 33% of the protein (PVS1_strong). This variant is absent in 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. There are no cybrids, single fiber studies, or other functional assays reported on this variant. This variant meets criteria to be classified as uncertain significance for primary mitochondrial disease. After extensive discussion, this Expert Panel agreed with this classification given low heteroplasmy levels in the only reported case with a severe phenotype, limited ability of technology used at the time to accurately report heteroplasmy, and because other genetic etiologies were not excluded in the only case reported. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on January 22, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID:32906214): PVS1_strong, PM2_supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA120606/MONDO:0044970/015

• Frequency: Mitomap GenBank: Absent
• Consequence: MT-CO2 ENST00000361739.1 frameshift
• Clinical Significance: Uncertain significance reviewed by expert panel P:1 U:1 Lactic-Acidosis
• Conservation: PhyloP100: 7.66
• Publications: 1 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]

MT-CO2 Gene-Disease associations (from GenCC):

• mitochondrial disease

  Inheritance: Mitochondrial Classification: DEFINITIVE Submitted by: ClinGen
• cytochrome-c oxidase deficiency disease

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• MELAS syndrome

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

  Inheritance: Mitochondrial Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COX2	unassigned_transcript_4802	c.458_459delTA	p.Met153fs	frameshift_variant	Exon 1 of 1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MT-CO2	ENST00000361739.1	c.458_459delTA	p.Met153fs	frameshift_variant	Exon 1 of 1	6		ENSP00000354876.1

Frequencies

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

Mitomap

Disease(s): Lactic-Acidosis

Status: Reported-[VUS]

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

Mitochondrial complex IV deficiency, nuclear type 1 Pathogenic:1

Jul 22, 2001

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Mitochondrial disease Uncertain:1

Jan 22, 2024

ClinGen Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel, ClinGen

Significance: Uncertain significance

Review Status: reviewed by expert panel

Collection Method: curation

The m.8043_8044del frameshift variant in MT-CO2 has been reported in one individual with primary mitochondrial disease to date, in an infant with severe lactic acidosis who died at 12 days old (PMID: 11471180). Complex IV deficiency was noted in skeletal and cardiac muscle. The variant was present at 20% heteroplasmy in skeletal muscle, 17% in cardiac muscle, 14% in lung tissue, 14% in liver, and 11.5% in skin. The variant was not assessed in proband’s blood and was undetectable in mother’s blood. Of note, nuclear genetic etiologies were not evaluated in this case. This variant causes a premature stop in the MT-CO2 gene resulting in truncation of 33% of the protein (PVS1_strong). This variant is absent in 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. There are no cybrids, single fiber studies, or other functional assays reported on this variant. This variant meets criteria to be classified as uncertain significance for primary mitochondrial disease. After extensive discussion, this Expert Panel agreed with this classification given low heteroplasmy levels in the only reported case with a severe phenotype, limited ability of technology used at the time to accurately report heteroplasmy, and because other genetic etiologies were not excluded in the only case reported. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on January 22, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PVS1_strong, PM2_supporting. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.7

Other links and lift over

dbSNP: rs199474828; hg19: chrM-8042;