Variant: m.15150G>A

CA120619

9681 (ClinVar)

Gene: N/A

Condition: mitochondrial disease

Inheritance Mode: Mitochondrial inheritance

UUID: 56c6a8d4-ecd0-4017-b0b6-c4c90ca1eede

Approved on: 2024-01-08

Published on: 2024-11-15

HGVS expressions

NC_012920.1:m.15150G>A
J01415.2:m.15150G>A
ENST00000361789.2:c.404G>A

Likely Pathogenic

• Met criteria codes: PM2_Supporting PVS1_Strong

• Not Met criteria codes: PM6 BP4 PS2 PS4 PS3 PP3

Expert Panel

Mitochondrial Diseases VCEP

Criteria Specification Information

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

Evidence submitted by expert panel

Mitochondrial Diseases VCEP

The m.15150G>A (p.W135Ter) variant in MT-CYB has been reported in one individual to date, in an individual with exercise intolerance from childhood (PMID: 11464242). The variant was present at 60% heteroplasmy in skeletal muscle and was undetectable in blood and skin fibroblasts. Complex III activity was reduced in muscle and normal in leukocytes and skin fibroblasts. The variant was undetectable in blood from the healthy mother, however the significance of this is unclear given the variant was also undetectable in blood from the proband. There are no additional 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). There are no in silico predictors for this type of variant in mitochondrial DNA. This variant results in a significant truncation (65%) of the MT-CYB protein (PVS1_strong). There are no cybrids, single fiber studies, or other functional assays reported on this variant. In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease however, after extensive discussion, this Expert Panel elected to modify the classification to likely pathogenic given the consistent biochemical phenotype and likely deleterious nature of this truncating variant. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on January 8, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PVS1_strong, PM2_supporting.

Met criteria codes

• PM2_Supporting: This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting).
• PVS1_Strong: This variant results in a significant truncation (65%) of the MT-CYB protein (PVS1_strong).

Not Met criteria codes

• PM6: The variant was undetectable in blood from the healthy mother, however the significance of this is unclear given the variant was also absent in blood from the proband.
• BP4: There are no in silico predictors for this type of variant in mitochondrial DNA.
• PS2: The variant was undetectable in blood from the healthy mother, however the significance of this is unclear given the variant was also absent in blood from the proband.
• PS4: The m.15150G>A (p.W135Ter) variant in MT-CYB has been reported in one individual to date, in an individual with exercise intolerance from each childhood (PMID: 11464242). The variant was present at 60% heteroplasmy in skeletal muscle and was undetectable in blood and skin fibroblasts. Complex III activity was reduced in muscle and normal in leukocytes and skin fibroblasts.
• PS3: No cybrid or single fiber studies were performed, although detailed muscle enzymology and Western blots were performed. Complex III was shown to be severely defective in muscle but normal in leukocytes and skin fibroblasts. Despite the presence of uridine and pyruvate supplementing the culture medium, mutation G15150A was undetectable in the myoblasts obtained from patient muscle.
• PP3: There are no in silico predictors for this type of variant in mitochondrial DNA.