Variant: m.12811T>C

65510 (ClinVar)

Gene: MT-ND5

Condition: mitochondrial disease

Inheritance Mode: Mitochondrial inheritance

UUID: 3f63f1f9-2018-4522-b35f-f7430361d8ec

HGVS expressions

NC_012920.1:m.12811T>C

Benign

• Met criteria codes: BP4 BA1

• Not Met criteria codes: PS4 PS3 PS2 PP3 PM6 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.12811T>C (p. Y159H) variant in MT-ND5 was reviewed by the Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel on April 17, 2023. This variant has not been reported in the medical literature as an individual cause of primary mitochondrial disease to our knowledge. However, there are nine cases reported that have this variant and the common Leber Hereditary Optic Neuropathy (LHON) variant, m.11778G>A, and one case with this variant and the m.3460G>A common LHON variant (PMIDs: 17406640, 17434142, 19026397). While this variant has been reported to be a modifier or secondary variant for LHON, assessment of such variants is outside the scope of this curation. The computational predictor APOGEE gives a consensus rating of 0.32 (Min=0, Max=1), supporting a neutral effect of this variant on function (BP4). This variant is present in population databases including MITOMAP’s GenBank sequences (674/59,389; 1.135%), in the Helix dataset (1,274/195,983; 0.650%; includes 1274 homoplasmic occurrences and 14 heteroplasmic occurrences and seen in haplogroups H, M, A, K, W, D, L2, T), and in gnomAD v3.1.2 (328/56,429; 0.581%; includes 328 homoplasmic occurrences across individuals of East Asian, European (non-Finnish), Latino, and South Asian descent; BA1). There are no cybrids, single fiber studies, or other functional assays reported on this variant. In summary, this variant meets criteria to be classified as benign 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 April 17, 2023. Mitochondrial DNA-specific ACMG/AMP criteria applied: BP4, BA1.

Met criteria codes

• BP4: The computational predictor APOGEE gives a consensus rating of 0.32 (Min=0, Max=1), evidence that does not predict a damaging effect on gene function (BP4).
• BA1: Current criteria > 1%. Mitomap 674/59,389 FL Seq (1.135%); Helix 1274/195,983 seq (0.650%) 1274 homoplasmic and 14 heteroplasmic; haplogroups H, M, A, K, W, D, L2, T; gnomAD 328/56,429 (0.581%) 328 homoplasmic East Asian, European (non Finnish), Latino, and S Asian.

Not Met criteria codes

• PS4: The MT-ND5 gene m.12811 T>C has not been reported in the literature as an independent cause of mitochondrial disease. There are 9 cases reported with the m.11778 A>A and 1 case with m.3460 G>A with this variant in Leber's hereditary neuropathy (LHON_ (PMID: 17406640, 17434142, 19026397).
• PS3: There are no cybrids, single fiber studies, or other functional assays reported on this variant.
• PS2: There are no reported cases.
• PP3: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PM6: There are no reported cases.
• PM2: Mitomap 674/59,389 FL Seq (1.135%); Helix 1274/195,983 seq (0.650%) 1274 homoplasmic and 14 heteroplasmic; haplogroups H, M, A, K, W, D, L2, T; gnomAD 328/56,429 (0.581%) 328 homoplasmic East Asian, European (non Finnish), Latino, and S Asian.

Approved on: 2023-04-17

Published on: 2023-05-19