Variant: NC_012920.1(MT-TS1):m.7445A>T

CA414792846

631469 (ClinVar)

Gene: N/A

Condition: mitochondrial disease

Inheritance Mode: Mitochondrial inheritance

UUID: cbbd381c-36c9-46a4-91be-03c07cf8affa

Approved on: 2024-07-08

Published on: 2024-12-09

HGVS expressions

NC_012920.1:m.7445A>T
J01415.2:m.7445A>T
ENST00000361624.2:c.1542A>T

Uncertain Significance

• Met criteria codes: PM5_Supporting

• Not Met criteria codes: PS4 PP3 PM2

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.7445A>T (p.*514S) variant in MT-CO1 has been reported in one individual with primary mitochondrial disease to date (PMID: 18639500). This person was Chinese and had severe hearing loss onset at age one year. There was no known precipitating event. The variant was homoplasmic in blood. There was no family history of hearing loss. This variant is present in population databases (Mitomap's 51,863 sequences: AF=0.049%; Helix's 196,554 sequences: AF=0.002%; gnomAD v3.1.2: absent). 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. Another variant at this position has been classified as pathogenic – m.7445A>G (PM5_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 July 8, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PM5_supporting.

Met criteria codes

• PM5_Supporting: Another variant at this position has been classified as pathogenic – m.7445A>G (PM5_supporting).

Not Met criteria codes

• PS4: The m.7445A>T (p.*514S) variant in MT-CO1 has been reported in one individual with primary mitochondrial disease to date (PMID: 18639500). This person was Chinese and had severe hearing loss onset at age one year. There was no known precipitating event. The variant was homoplasmic in blood. There was no family history of hearing loss.
• 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.
• PM2: This variant is present in population databases (Mitomap's 51,863 sequences: AF=0.049%; Helix's 196,554 sequences: AF=0.002%; gnomAD v3.1.2: absent).