Variant: NC_012920.1:m.7443A>G

CA347798

40158 (ClinVar)

Gene: MT-CO1

Condition: mitochondrial disease

Inheritance Mode: Mitochondrial inheritance

UUID: 90cab362-378c-4d46-b6d3-5ad3760fc316

Approved on: 2024-07-08

Published on: 2024-12-09

HGVS expressions

NC_012920.1:m.7443A>G
J01415.2:m.7443A>G
ENST00000361624.2:c.1540A>G

Uncertain Significance

• Met criteria codes: PM2_Supporting PS3_Supporting

• Not Met criteria codes: PS4 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.7443A>G (p.*514G) variant in MT-CO1 has been reported in one individual with primary mitochondrial disease to date (PMID: 10577941), in a child enrolled at the School for Deaf and Blind in Mongolia. He was reported to have been deaf since infancy. The variant appeared to be homoplasmic. Information was not provided on the family history of this individual. There are no additional case reports to our knowledge. There are several occurrences of this variant in population databases (Mitomap: 1/61,134, gnomAD: 1/56,434, Helix: 4/195,893). Although there are several occurrences, the frequency is still low (PM2_supporting). There are no in-silico prediction tools for a stop-loss variant in mitochondrial DNA, although this variant would not be expected to cause run-through due to the excision of the tRNA immediately adjacent. Functional studies showed inefficient processing (29% of wild type) by tRNAseZ in the presence of this variant (PS3_supporting; PMID: 16361254). 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 8, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS3_supporting, PM2_supporting.

Met criteria codes

• PM2_Supporting: There are several occurrences in population databases (Mitomap: 1/61,134, gnomAD: 1/56,434, Helix: 4/195,893). Although there are several occurrences, the frequency is still low (PM2_supporting).
• PS3_Supporting: Yan et al 2006 (PMID 16361254) demonstrated inefficient processing (29% of WT) by tRNAseZ in the presence of this mutation.

Not Met criteria codes

• PS4: The MT-CO1 m.7443A>G (*514G) variant was reported in one student of ~400 from the School for Deaf and Blind in Mongolia. He was reported to have been deaf since infancy (Pandya et al 1999, PMID 10577941). The variant appeared to be homoplasmic by Sequenase PCR sequencing. Both m.1555A>G and m.7445A>G were absent. No family information was reported for this patient and no other mitochondrial disease cases were found with m.7443A>G in our review of the literature.
• PP3: There are no in-silico prediction tools for a stop-loss variant in mitochondrial DNA, although this variant would not be expected to cause run-through due to the excision of the tRNA immediately adjacent.