Variant: m.3249G>A

CA254840

9599 (ClinVar)

Gene: N/A

Condition: mitochondrial disease

Inheritance Mode: Mitochondrial inheritance

UUID: 808ef342-e0b4-4792-b7c2-e4679f1f0218

Approved on: 2024-04-22

Published on: 2024-11-20

HGVS expressions

NC_012920.1:m.3249G>A
J01415.2:m.3249G>A

Uncertain Significance

• Met criteria codes: PP1 PS3_Supporting PM2_Supporting

• Not Met criteria codes: PP3 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.3249G>A variant in MT-TL1 has been reported in one individual to date, in a man with progressive vision loss, hearing loss, myopathy, and ragged red and COX-negative fibers, whose presentation was reminiscent of Kearns Sayre syndrome (PMID: 11448301). The variant was present at 85% heteroplasmy in skeletal muscle and 45% in leukocytes in the proband, 5% in the blood of the healthy mother, and was undetectable in blood from a healthy sister (PP1). This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). Computational predictors are conflicting (MitoTIP: 39.3%; HmtVAR: 0.45). There are no cybrids or single fiber studies reported on this variant, however two processing studies have shown termination blockage (PMID: 20550934) and RNAseP binding interference (PMID: 33380464), and this variant was also found to negatively impact 5' end cleavage and m1A9 methylation (PMID: 33380464; PS3_supporting). 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 April 22, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PP1, PM2_supporting, PS3_supporting.

Met criteria codes

• PP1: The variant was present at 85% heteroplasmy in skeletal muscle and 45% in leukocytes in the proband, 5% in the blood of the healthy mother, and was undetectable in blood from a healthy sister (PP1).
• PS3_Supporting: There are no cybrids or single fiber studies reported on this variant, however two processing studies have shown termination blockage (PMID: 20550934) and RNAseP binding interference (PMID: 33380464), and this variant was also found to negatively impact 5' end cleavage and m1A9 methylation (PMID: 33380464; PS3_supporting).
• PM2_Supporting: This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting).

Not Met criteria codes

• PP3: In-silico predictors for m.3249G>A were conflicting: MitoTip 0.393 “Possibly Benign” (<0.5) versus HmtVar 0.45 “Pathogenic” (<0.35).
• PS4: The m.3249G>A variant in MT-TL1 has been reported in one individual to date, in an individual with progressive vision loss, hearing loss, myopathy, and ragged red and COX-negative fibers, whose presentation was reminiscent of Kearns Sayre syndrome (PMID: 11448301).