Variant: m.15967G>A

CA120550

9572 (ClinVar)

Gene: N/A

Condition: mitochondrial disease

Inheritance Mode: Mitochondrial inheritance

UUID: 187884bf-5ab7-4e8c-8779-25f0b6075914

Approved on: 2024-05-13

Published on: 2024-12-04

HGVS expressions

NC_012920.1:m.15967G>A
J01415.2:m.15967G>A

Uncertain Significance

• Met criteria codes: PP3 PS3_Supporting PM6_Supporting PM2_Supporting

• Not Met criteria codes: PS4

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.15967G>A variant in MT-TP has been reported in one individual with primary mitochondrial disease to date (PMID: 19273760). She had adult-onset myoclonic jerks, seizures, myopathy, cerebellar ataxia, hearing loss, cataracts, retinal pigmentary changes, and ragged red fibers on muscle biopsy. Brain imaging showed changes in the cerebral white matter, basal ganglia, and thalami, in addition to cerebral and cerebellar atrophy. This variant occurred de novo in the single reported individual (absent in blood and urine from mother and two healthy sisters; PM6_supporting, PMID: 19273760). This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). The computational predictor MitoTIP suggests this variant is deleterious (78.9 percentile) and HmtVAR predicts it to be deleterious with a score of 0.65 (PP3). It should be noted that the low conservation of this variant (35.56% in Mitomap) is misleading due to the absence of this position in many species. Among species with a nucleotide at this position, the conservation is 84%. Single fiber testing showed higher levels of the variant in COX-deficient fibers (98.80%, standard deviation 0.89%) than in COX-positive fibers (31.1%, standard deviation 11.23%; PS3_supporting, PMID: 19273760). In summary, this variant meets criteria to be classified as uncertain significance 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 May 13, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PM6_supporting, PP3, PS3_supporting, PM2_supporting.

Met criteria codes

• PP3: In-silico predictors report the variant as damaging: MitoTip, 0.789, “Likely Pathogenic”; HmtVar, 0.65 “Pathogenic”. It should be noted that the low conservation of this variant (35.56% in Mitomap) is misleading due to the absence of this position in many species. Among species with a nucleotide at this position, the conservation is 84%.
• PS3_Supporting: Single fiber testing showed higher levels of the variant in COX-deficient fibers (98.80%, standard deviation 0.89%) than in COX-positive fibers (31.1%, standard deviation 11.23%; PS3_supporting, PMID: 19273760).
• PM6_Supporting: This variant occurred de novo in the single reported individual (absent in blood and urine from mother and two healthy sisters; PM6_supporting, PMID: 19273760).
• PM2_Supporting: This variant is absent in the Mitomap (0/61168), gnomAD (0/56434), and Helix ( 0/195893) databases as of April 20, 2024.

Not Met criteria codes

• PS4: The m.15967G>A variant in MT-TP has been reported in one individual with primary mitochondrial disease to date (PMID: 19273760). She had adult-onset myoclonic jerks, seizures, myopathy, cerebellar ataxia, hearing loss, cataracts, retinal pigmentary changes, and ragged red fibers on muscle biopsy. Brain imaging showed changes in the cerebral white matter, basal ganglia, and thalami, in addition to cerebral and cerebellar atrophy.