Variant: m.14482C>G

CA344824

65513 (ClinVar)

Gene: MT-ND6

Condition: mitochondrial disease

Inheritance Mode: Mitochondrial inheritance

UUID: 80e94925-06b6-4d9b-bc32-b106d95802aa

HGVS expressions

NC_012920.1:m.14482C>G
J01415.2:m.14482C>G
ENST00000361681.2:n.192G>C

Likely Pathogenic

The Expert Panel has overridden the computationally generated classification - "Uncertain Significance - Insufficient Evidence"

• Met criteria codes: PM2_Supporting PS1 PP3 PM5

• Not Met criteria codes: PS3 PS2 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.14482C>G (p.M64I) variant in MT-ND6 has been reported in one proband from an extended consanguineous kindred with primary mitochondrial disease. The predominant feature in this family was bilateral optic atrophy consistent with Leber Hereditary Optic Neuropathy (LHON). The variant was present at homoplasmy in affected and unaffected individuals from this family and, when affected, the age of onset was early adulthood (PMID: 9443868). It appears some individuals from this family were reported multiple times (PMIDs: 21887510, 8742999). There are no reported de novo occurrences of this variant to our knowledge. The variant was homoplasmic in family members of the only reported proband, precluding consideration for segregation evidence. This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). Another variant at this nucleotide position leading to the same amino acid change was classified as likely pathogenic by this expert panel, m.14482C>A (p.M64I, PS1). Furthermore, a different variant at this amino acid position leading to a different amino acid change is one of the most common causes of LHON and is a known pathogenic variant, m.14484T>C (p.M64V, PM5). The computational predictor APOGEE gives a consensus rating of pathogenic with a score of 0.96 (Min=0, Max=1), which predicts a damaging effect on gene function (PP3). There are no cybrid studies, single fiber studies, or other functional assays reported for this variant. In summary, this variant meets criteria to be classified as likely pathogenic for primary mitochondrial disease inherited in a mitochondrial manner. We note that one expert on this panel felt uncertain significance was a more appropriate classification given the only reported family was consanguineous and nuclear genetic etiologies were not assessed. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on July 11, 2022. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PM2_supporting, PS1, PM5, PP3.

Met criteria codes

• PM2_Supporting: This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting).
• PS1: Another variant at this nucleotide position leading to the same amino acid change was classified as likely pathogenic by this expert panel, m.14482C>A (p.M64I, PS1).
• PP3: The computational predictor APOGEE gives a consensus rating of pathogenic with a score of 0.96 (Min=0, Max=1), which predicts a damaging effect on gene function (PP3).
• PM5: Furthermore, a different variant at this amino acid position leading to a different amino acid change is one of the most common causes of LHON and is a known pathogenic variant, m.14484T>C (p.M64V, PM5).

Not Met criteria codes

• PS3: There are no cybrid studies, single fiber studies, or other functional assays reported for this variant.
• PS2: There are no reported de novo occurrences of this variant to our knowledge.
• PS4: The m.14482C>G (p.M64I) variant in MT-ND6 has been reported in one proband from an extended consanguineous kindred with primary mitochondrial disease. The predominant feature in this family was bilateral optic atrophy consistent with Leber Hereditary Optic Neuropathy (LHON). The variant was present at homoplasmy in affected and unaffected individuals from this family and, when affected, the age of onset was early adulthood (PMID: 9443868). It appears some individuals from this family were reported multiple times (PMIDs: 21887510, 8742999).
• PP1: The variant was homoplasmic in family members of the only reported proband, precluding consideration for segregation evidence.
• PM6: There are no reported de novo occurrences of this variant to our knowledge.

Approved on: 2022-07-11

Published on: 2023-03-29