rs199474825

Variant names:

• chrM-7587-T-C
• rs199474825
• ENST00000361739.1:c.2T>C

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PVS1_Strong PS3_Supporting PP3 PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The m.7587T>C (p.M1T) variant in MT-CO2 has been reported in one family with primary mitochondrial disease to date (PMID:10205264). Affected individuals in this family include a 57-year-old woman with fatigue and unsteady gait and her more severely affected son who was nonambulatory and had cognitive impairment, optic atrophy, pigmentary retinopathy, and distal muscle wasting. The variant was present at 67% heteroplasmy in the muscle of the mother and at 91% in muscle of her affected son. There are no individuals reported with de novo occurrences of this variant to our knowledge. This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). The computational predictor APOGEE gives a consensus rating of pathogenic with a score of 0.79 (Min=0, Max=1; APOGEE2 score is 0.875), which predicts a damaging effect on gene function (PP3). This initiation codon variant results in a significant truncation of the MT-CO2 protein (PVS1_strong). Single fiber testing showed higher levels of the variant in COX-negative (near homoplasmy) than in COX-positive fibers (17–52%; PS3_supporting, PMID:10205264). 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 March 11, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID:32906214): PVS1_strong, PP3, PS3_supporting, PM2_supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA120604/MONDO:0044970/014

• Frequency: Mitomap GenBank: Absent
• Consequence: MT-CO2 ENST00000361739.1 start_lost
• Scores: Apogee2 Pathogenic 0.88
• Clinical Significance: Likely pathogenic reviewed by expert panel P:2 Mitochondrial-Encephalomyopathy
• Conservation: PhyloP100: 7.73
• Publications: 2 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-CO1 (HGNC:7419): (mitochondrially encoded cytochrome c oxidase I) Contributes to cytochrome-c oxidase activity. Predicted to be involved in electron transport coupled proton transport and mitochondrial electron transport, cytochrome c to oxygen. Part of mitochondrial respiratory chain complex III and mitochondrial respiratory chain complex IV. [provided by Alliance of Genome Resources, Apr 2022]

TRNS1 (HGNC:7497): (mitochondrially encoded tRNA serine 1 (UCN))

TRND (HGNC:7478): (mitochondrially encoded tRNA aspartic acid)

TRND Gene-Disease associations (from GenCC):

• mitochondrial disease

  Inheritance: Mitochondrial Classification: MODERATE Submitted by: ClinGen

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 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.
• PP3: 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.2T>C	p.Met1?	start_lost	Exon 1 of 1
TRNS1	unassigned_transcript_4800	c.-73A>G		upstream_gene_variant
COX1	unassigned_transcript_4799	c.*142T>C		downstream_gene_variant
TRND	unassigned_transcript_4801	c.*2T>C		downstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MT-CO2	ENST00000361739.1	c.2T>C	p.Met1?	start_lost	Exon 1 of 1	6		ENSP00000354876.1
MT-CO1	ENST00000361624.2	c.*142T>C		downstream_gene_variant		6		ENSP00000354499.2
MT-TS1	ENST00000387416.2	n.-73A>G		upstream_gene_variant		6
MT-TD	ENST00000387419.1	n.*2T>C		downstream_gene_variant		6

Frequencies

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

Alfa AF: 0.00 Hom.: 0

Mitomap

Disease(s): Mitochondrial-Encephalomyopathy

Status: Reported

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: reviewed by expert panel

Submissions by phenotype

Mitochondrial complex IV deficiency, nuclear type 1 Pathogenic:1

May 01, 1999

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Mitochondrial disease Pathogenic:1

Mar 11, 2024

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

Significance: Likely pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The m.7587T>C (p.M1T) variant in MT-CO2 has been reported in one family with primary mitochondrial disease to date (PMID: 10205264). Affected individuals in this family include a 57-year-old woman with fatigue and unsteady gait and her more severely affected son who was nonambulatory and had cognitive impairment, optic atrophy, pigmentary retinopathy, and distal muscle wasting. The variant was present at 67% heteroplasmy in the muscle of the mother and at 91% in muscle of her affected son. There are no individuals reported with de novo occurrences of this variant to our knowledge. This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). The computational predictor APOGEE gives a consensus rating of pathogenic with a score of 0.79 (Min=0, Max=1; APOGEE2 score is 0.875), which predicts a damaging effect on gene function (PP3). This initiation codon variant results in a significant truncation of the MT-CO2 protein (PVS1_strong). Single fiber testing showed higher levels of the variant in COX-negative (near homoplasmy) than in COX-positive fibers (17–52%; PS3_supporting, PMID: 10205264). 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 March 11, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PVS1_strong, PP3, PS3_supporting, PM2_supporting. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
Apogee2	Pathogenic	0.88
Hmtvar	Pathogenic	0.79
BayesDel_addAF	Benign	-0.020	T
DEOGEN2	Benign	0.23	T
LIST_S2	Uncertain	0.90	D
PhyloP100		7.7
PROVEAN	Pathogenic	-5.7	D
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
GERP RS		4.3
Varity_R		0.76
Mutation Taster		=22/178	disease causing

Other links and lift over

dbSNP: rs199474825; hg19: chrM-7588;