Evidence Repository
The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]
  • The variant label for this record ("m.7587T>C") does not appear to be in HGVS format
  • Despite there being a valid 'cspec' property in the messages there's a discrepancy in message contents and CSPEC data: * Message Gene: MT-CO2 CSPEC Genes: [] * Message MONDOs: MONDO:0044970 CSPEC MONDO: []
  • No CSPEC computed assertion could be determined for this classification!

Variant: m.7587T>C

CA120604

9658 (ClinVar)

Gene: MT-CO2
Condition: mitochondrial disease
Inheritance Mode: Mitochondrial inheritance
Link to MONDO
UUID: 2338fdba-0964-469b-9310-a485936ee040
Approved on: 2024-03-11
Published on: 2024-11-19

HGVS expressions

NC_012920.1:m.7587T>C
J01415.2:m.7587T>C
ENST00000361739.1:c.2T>C

Likely Pathogenic

Met criteria codes 4
PVS1_Strong PP3 PM2_Supporting PS3_Supporting
Not Met criteria codes 5
PS2 PS4 PP4 PP1 PM6

Evidence Links 1

Expert Panel

Criteria Specification Information

Criteria Specification: ClinGen Mitochondrial Disease Nuclear and Mitochondrial Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 1_mtDNA

Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
Mitochondrial Diseases VCEP
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.
Met criteria codes
PVS1_Strong
This initiation codon variant results in a significant truncation of the MT-CO2 protein (PVS1_strong).
PP3
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).
PM2_Supporting
This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting).
PS3_Supporting
A single fiber study of the patient’s muscle showed clearly that the m.7587T>C variant segregated with a biochemical defect: the C allele was at much higher load in COX-negative fibers than in COX-positive fibers (PMID 10205264).
A single fiber study of the patient’s muscle showed clearly that the m.7587T>C variant segregated with a biochemical defect: the C allele was at much higher load in COX-negative fibers than in COX-positive fibers PubMed:10205264
Not Met criteria codes
PS2
There are no individuals reported with de novo occurrences of this variant to our knowledge.
PS4
The m.7587T>C variant in MT-CO2 has been reported in only one family to date, a 57-year-old woman with fatigue and unsteady gait with a severely affected, wheelchair-bound son. He was severely cognitively impaired with bilateral optic atrophy, pigmentary retinopathy, a marked decrease in color vision, and mild distal-muscle wasting. An older son was clinically unaffected at age 30 (PMID 10205264).
PP4
The mutation was shown to cause a decrease in COX activity when the mutant load was >55%–65%. In fibroblasts from the affected son, which contained >95% mutated mtDNA, there was no detectable synthesis or any steady-state level of COX II. However, nuclear causes of isolated COX deficiency were not ruled out (PMID 10205264).
PP1
Only one segregation of m.7587T>C was observed in the family: the mildly affected mom had 67% heteroplasmy in muscle, while her severely affected son had 91% in muscle. The unaffected old son declined testing (PMID 10205264).
PM6
There are no individuals reported with de novo occurrences of this variant to our knowledge.
Curation History
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