Variant: NC_012920.1(MT-CYB):m.9997T>A

CA913182452

690090 (ClinVar)

Gene: N/A

Condition: mitochondrial disease

Inheritance Mode: Mitochondrial inheritance

UUID: cc45edfc-71bc-44d4-8406-df4c518fda9c

Approved on: 2024-07-22

Published on: 2024-08-08

HGVS expressions

NC_012920.1:m.9997T>A
J01415.2:m.9997T>A

Uncertain Significance

• Met criteria codes: PM2_Supporting PP3

• Not Met criteria codes: PS3 PS4 PP1 PM6

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.9997T>A variant in MT-TG has been reported in one individual to date, however clinical details were not provided (PMID: 31965079). Similarly, there is no available information on segregation in family members or de novo status. It is possible this individual was reported in a poster abstract submitted by Roggenbuck et al., 2016 (https://www.neurology.org/doi/10.1212/WNL.86.16_supplement.P5.016), but this has not been confirmed. The individual reported with this variant in this abstract was a man with exercise intolerance, myalgia, muscle weakness, ptosis, neuropathy, dilated cardiomyopathy, and renal disease. Respiratory chain enzyme testing on muscle showed low cytochrome c oxidase activity but exact values were not provided. The variant was reported to be present at homoplasmy in the proband and was also reported in other maternal family members with varying clinical features, however details were not provided. This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). There are no cybrids, single fiber studies, or other functional assays reported on this variant. The computational predictor MitoTIP suggests this variant is deleterious (95.2 percentile) and HmtVAR predicts it to be deleterious with a score of 0.35 (PP3). 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 July 22, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PM2_supporting, PP3.

Met criteria codes

• PM2_Supporting: This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting).
• PP3: The computational predictor MitoTIP suggests this variant is deleterious (95.2 percentile) and HmtVAR predicts it to be deleterious with a score of 0.35 (PP3).

Not Met criteria codes

• PS3: There are no cybrids, single fiber studies, or other functional assays reported on this variant.
• PS4: The m.9997T>A variant in MT-TG has been reported in one individual to date, however clinical details were not provided (PMID: 31965079). Similarly, there is no available information on segregation in family members or de novo status. It is possible this individual was reported in a poster abstract submitted by Roggenbuck et al., 2016 (https://www.neurology.org/doi/10.1212/WNL.86.16_supplement.P5.016), but this has not been confirmed. The individual reported with this variant in this abstract was a man with exercise intolerance, myalgia, muscle weakness, ptosis, neuropathy, dilated cardiomyopathy, and renal disease. Respiratory chain enzyme testing on muscle showed low cytochrome c oxidase activity but exact values were not provided.
• PP1: The variant was reported to be present at homoplasmy in the proband and was also reported in other maternal family members with varying clinical features, however details were not provided.
• PM6: The variant was reported to be present at homoplasmy in the proband and was also reported in other maternal family members with varying clinical features, however details were not provided.