Variant: NC_012920.1:m.13379A>C

CA414817724

Gene: N/A

Condition: mitochondrial disease

Inheritance Mode: Mitochondrial inheritance

UUID: 6615f92f-9cef-49d4-907a-f251742f99d8

HGVS expressions

NC_012920.1:m.13379A>C
J01415.2:m.13379A>C
ENST00000361567.2:n.1043A>C

Uncertain Significance

• Met criteria codes: PP3 PM2_Supporting

• Not Met criteria codes: PS4 PS3 PS2 PS1 PP1 PM6 PM5 PVS1

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.13379A>C (p.H348P) variant in MT-ND5 has been reported in one individual from one family (PMID: 17003408), in a male with LHON. The variant was present at homoplasmy in blood and haplogroup was M1. Although it is reported in this paper that this proband had a family history of poor vision, no details are provided. This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). The computational predictor APOGEE gives a consensus rating of pathogenic with a score of 0.80 (Min=0, Max=1), which predicts a damaging effect on gene function (PP3). There are no functional studies reported on this variant. 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 Mitochondrial Disease Variant Curation Expert Panel on May 3, 2022. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PM2_supporting, PP3.

Met criteria codes

• PP3: The computational predictor APOGEE gives a consensus rating of pathogenic with a score of 0.80 (Min=0, Max=1), which predicts a damaging effect on gene function (PP3).
• PM2_Supporting: This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting).

Not Met criteria codes

• PS4: The m.13379A>C (p.H348P) variant in MT-ND5 has been reported in one individual from one family (PMID: 17003408), in a male with LHON. The variant was present at homoplasmy in blood and haplogroup was M1.
• PS3: There are no functional studies reported for this variant.
• PS2: Family history information is not reported for the single case reported (Abu-Amero et al., 2006).
• PS1: No other variants resulting in the same amino acid change are reported.
• PP1: Family history information is not reported for the single case reported (Abu-Amero et al., 2006).
• PM6: Family history information is not reported for the single case reported (Abu-Amero et al., 2006).
• PM5: m.13379A>G (p.H348R) has been reported to be associated with LHON, however evidence did not meet criteria to be classified as pathogenic or likely pathogenic.
• PVS1: This is a missense variant.

Approved on: 2022-06-30

Published on: 2022-06-30