Variant: NC_012920.1(MT-ND6):m.14513_14514del

CA915952148

800503 (ClinVar)

Gene: MT-ND6

Condition: mitochondrial disease

Inheritance Mode: Mitochondrial inheritance

UUID: 693e8f8b-8f0b-4970-9e4d-ab826bec1ffd

Approved on: 2023-12-21

Published on: 2024-03-15

HGVS expressions

NC_012920.1:m.14513_14514del
J01415.2:m.14513_14514del
ENST00000361681.2:c.161_162del

Likely Pathogenic

• Met criteria codes: PM6_Supporting PS3_Supporting PM2_Supporting PVS1_Strong

• Not Met criteria codes: BP4 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.14513_14514delAT (p.Met54SerfsTer7) variant in MT-ND6 has been reported in one individual to date, in a man with mitochondrial myopathy characterized by adolescent onset exercise intolerance and muscle weakness as well as ptosis, reduced muscle bulk, and lumbar lordosis. Muscle biopsy showed that 13% of muscle fibers were ragged red fibers (RRF) and >75% of fibers showed a complete loss of NDUFB8 immunoreactivity associated with preserved COX-I immunoreactivity (PMID: 32158465). The variant was present at 76% heteroplasmy in skeletal muscle, 10% in urine, and was undetectable in blood and buccal samples. As this is the only case reported to date, PS4 could not be applied. The variant was absent in blood, buccal, and urine samples from his healthy mother (PM6_supporting). Computational predictors are not applicable for this variant type precluding consideration for PP3 or BP4. This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). This variant results in a frame shift at position 54 and is predicted to result in loss of >10% protein (PVS1_strong). Single fiber testing showed that heteroplasmy levels in COX-positive ragged-red fibers was 90.9 ± 0.74% (n=21) and in COX-positive non-ragged-red fibers was 31.7 ± 9.6% (n=17; p < 0.0001; PS3_supporting; PMID: 32158465). In summary, this variant meets criteria to be classified as likely pathogenic 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 December 21, 2023. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PM6_supporting, PM2_supporting, PS3_supporting, PVS1_strong.

Met criteria codes

• PM6_Supporting: The variant was absent in blood, buccal, and urine samples from his healthy mother (PM6_supporting).
• PS3_Supporting: Single fiber testing showed that heteroplasmy levels in COX-positive ragged-red fibers was 90.9 ± 0.74% (n=21) and in COX-positive non-ragged-red fibers was 31.7 ± 9.6% (n=17; p < 0.0001; PS3_supporting; PMID: 32158465).
• PM2_Supporting: This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting).
• PVS1_Strong: This variant results in a frame shift at position 54 and is predicted to result in loss of >10% protein (PVS1_strong).

Not Met criteria codes

• BP4: Computational predictors are not applicable for this variant type precluding consideration for PP3 or BP4.
• PS4: The m.14513_14514delAT (p.Met54SerfsTer7) variant in MT-ND6 has been reported in one individual to date, in a man with mitochondrial myopathy characterized by adolescent onset exercise intolerance and muscle weakness as well as ptosis, reduced muscle bulk, and lumbar lordosis. Muscle biopsy showed that 13% of muscle fibers were ragged red fibers (RRF) and >75% of fibers showed a complete loss of NDUFB8 immunoreactivity associated with preserved COX-I immunoreactivity (PMID: 32158465). The variant was present at 76% heteroplasmy in skeletal muscle, 10% in urine, and was undetectable in blood and buccal samples. As this is the only case reported to date, PS4 could not be applied.
• PP3: Computational predictors are not applicable for this variant type precluding consideration for PP3 or BP4.