Variant: NC_012920.1:m.8418T>C

CA16040650

370050 (ClinVar)

Gene: N/A

Condition: mitochondrial disease

Inheritance Mode: Mitochondrial inheritance

UUID: f4765bbb-b4ab-46f6-ab9a-d73c06633ffb

Approved on: 2024-11-11

Published on: 2024-12-11

HGVS expressions

NC_012920.1:m.8418T>C
J01415.2:m.8418T>C
ENST00000361851.1:c.53T>C

Uncertain Significance

• Met criteria codes: BP4

• Not Met criteria codes: BS1 PS3 PS4 PP3 PP1 PM2 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.8418T>C (p.L18P) variant in MT-ATP8 has been reported in one individual with primary mitochondrial disease to date (PMID: 28027978), in a man with severe bilateral optic atrophy onset at age 44 years. The variant was present at homoplasmy in lymphocytes and fibroblasts. Family history information was not provided. There are no additional individuals reported with this variant to our knowledge. This variant is rare but present in population databases (Mitomap: 1/61,134; gnomAD v3.1.2: 5/46,432; Helix: 3/195,983) with a combined frequency of 0.00255%, which is slightly higher than the supporting pathogenic cutoff of 0.002% but lower than the frequency of 0.5-0.99% required for evidence of benign status. The computational predictor APOGEE gives a consensus rating of likely benign with a score of 0.175 (Min=0, Max=1), which predicts a neutral effect on gene function (BP4). There are no cybrids or single fiber studies reported on this variant although in-silico yeast modeling predicted this variant to destabilize the F0 domain of ATP8 (PMID: 37340059). 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 November 11, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): BP4.

Met criteria codes

• BP4: The APOGEE predictor tool scored this variant as “Likely Benign” with a raw score of 0.175 (BP4 met/PP3 not met)

Not Met criteria codes

• BS1: Variant m.8418T>C is present at low numbers in the Mitomap (1/611634), gnomAD (4/56432), and Helix (3/195983) databases as of November 7, 2024.The combined frequency was 0.00255%, slightly higher than the mandated supporting pathogenic cutoff of 0.002% but lower than the frequency of 0.5-0.99% required for strong benign.
• PS3: No cybrid or single-fiber studies were found in our review of the literature.
• PS4: A single case was reported in a male with severe bilateral optic neuropathy with age of onset at 44 years (PMID 28027978). The variant was homoplasmic in lymphocytes and fibroblasts with Sanger/ABI sequencing. An additional case was reported by a different group in ClinVar (370050), but no phenotypic or other details were given.
• PP3: The APOGEE predictor tool scored this variant as “Likely Benign” with a raw score of 0.175 (BP4 met/PP3 not met). Additionally, an in-silico yeast modeling study by Panja et al (PMID 37340059) predicted this variant would destabilize the F0 domain of ATP8.
• PP1: No families with multiple affected members with this variant were found in our review of the literature.
• PM2: Variant m.8418T>C is present at low numbers in the Mitomap (1/611634), gnomAD (4/56432), and Helix (3/195983) databases as of November 7, 2024.The combined frequency was 0.00255%, slightly higher than the mandated supporting pathogenic cutoff of 0.002% but lower than the frequency of 0.5-0.99% required for strong benign.
• PM6: Only a singleton case with no family information was found in our review of the literature.