Variant: m.3733G>A

CA340950

9736 (ClinVar)

Gene: MT-ND1

Condition: mitochondrial disease

Inheritance Mode: Mitochondrial inheritance

UUID: daa1d3fa-2de4-4e31-b8ad-af651dacd90e

Approved on: 2022-03-24

Published on: 2022-03-24

HGVS expressions

NC_012920.1:m.3733G>A
J01415.2:m.3733G>A
ENST00000361390.2:n.427G>A

Uncertain Significance

• Met criteria codes: PM2_Supporting PS4_Moderate PP3

• Not Met criteria codes: PM5 PM6 BP4 PS3 PS2 PS1 PP1

Expert Panel

Mitochondrial Diseases VCEP

Criteria Specification Information

Evidence submitted by expert panel

Mitochondrial Diseases VCEP

The m.3733G>A (p.E143K) variant in MT-ND1 has been reported in 10 individuals with features of primary mitochondrial disease from 4 families. Affected individuals had features consistent with LHON and LHON-plus (PS4_moderate; PMIDs: 15505787, 27177320, 29387390). There are no reports of de novo occurrences of this variant. Segregation was only seen in one family, with healthy mother having lower heteroplasmy levels than affected child (PMID: 15505787), however this does not meet criteria for PP1_supporting (minimum 2 segregations). There are 2 occurrences of this variant in GenBank dataset, however both are from individuals with known mitochondrial disease, and this variant is absent in gnomAD v3.1.2 and in Helix dataset (PM2_supporting). There are no functional studies reported. The computational predictor APOGEE gives a consensus rating of pathogenic with a score of 0.79 (Min=0, Max=1), which predicts a damaging effect on gene function (PP3). 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 March 22, 2022. Mitochondrial DNA-specific ACMG/AMP criteria applied: PS4_moderate, PM2_supporting, PP3.

Met criteria codes

• PM2_Supporting: There are 2 occurrences in GenBank dataset, however both appear to be from Achilli et al, where the first two cases reported in Valentino et al., 2004 are again discussed. This variant is absent in gnomAD and Helix datasets.
• PS4_Moderate: The m.3733G>A (p.E143K) variant in MT-ND1 has been reported in 4 individuals with primary mitochondrial disease who had features consistent with LHON (3/4) and LHON-plus (1/4); (PS4_moderate; PMIDs: 15505787, 27177320, 29387390).
• PP3: The computational predictor APOGEE gives a consensus rating of pathogenic with a score of 0.79 (Min=0, Max=1), which predicts a damaging effect on gene function (PP3).

Not Met criteria codes

• PM5: m.3733G>A (p.E143Q) has been reported in one individual (PMID: 22879922) however this variant is not definitively pathogenic.
• PM6: There are no reports of de novo occurrences.
• BP4: The computational predictor APOGEE gives a consensus rating of pathogenic with a score of 0.79 (Min=0, Max=1), which predicts a damaging effect on gene function (PP3).
• PS3: No functional validation has been performed to date.
• PS2: There are no reports of de novo occurrences.
• PS1: No other variants resulting in the same amino acid change have been reported.
• PP1: Segregation was only seen in one family, with healthy mother with lower heteroplasmy levels than affected child (PMID: 15505787), however this does not meet criteria for PP1_supporting (minimum 2 segregations).