Total submissions: 2
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Clin |
RCV004791203 | SCV005407783 | likely pathogenic | Mitochondrial disease | 2024-03-11 | reviewed by expert panel | 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. |
OMIM | RCV000010294 | SCV000030518 | pathogenic | Mitochondrial complex IV deficiency, nuclear type 1 | 1999-05-01 | no assertion criteria provided | literature only |