Variant: m.3700G>A

CA344828

65519 (ClinVar)

Gene: MT-ND1

Condition: mitochondrial disease

Inheritance Mode: Mitochondrial inheritance

UUID: 43629eb7-d1d0-459f-9f41-cb2b20199890

Approved on: 2022-03-24

Published on: 2022-03-24

HGVS expressions

NC_012920.1:m.3700G>A
J01415.2:m.3700G>A
ENST00000361390.2:n.394G>A

Uncertain Significance

• Met criteria codes: PS4_Supporting PM2_Supporting PP3

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

Expert Panel

Mitochondrial Diseases VCEP

Criteria Specification Information

Evidence submitted by expert panel

Mitochondrial Diseases VCEP

The m.3700G>A (p.A132T) variant in MT-ND1 has been reported in 3 individuals with primary mitochondrial disease who had features consistent with Leigh syndrome (1/3) and LHON (2/3; PS4_supporting; PMIDs: 30128709, 22879922, 12150954). There are no reports of de novo occurrences of this variant. There are no reports of testing in family members to date to consider for segregation. There are 3 occurrences of this variant in GenBank dataset, however 2/3 are from individuals with known mitochondrial disease. This variant is absent in gnomAD v3.1.2 and in Helix dataset therefore this variant is present at <1/50,000 healthy individuals (PM2_supporting). There are no functional studies reported. The computational predictor APOGEE gives a consensus rating of pathogenic with a score of 0.53 (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_supporting, PM2_supporting, PP3.

Met criteria codes

• PS4_Supporting: The m.3700G>A (p.A132T) variant in MT-ND1 has been reported in 3 individuals with primary mitochondrial disease who had features consistent with Leigh syndrome (1/3) and LHON (2/3; PS4_supporting; PMIDs: 30128709, 22879922, 12150954).
• PM2_Supporting: There are 3 occurrences in GenBank dataset, however 2/3 are from Achilli et al., 2012. This variant is absent in gnomAD and absent in Helix. Given one occurrence, this meets criteria as <1/50,000.
• PP3: The computational predictor APOGEE gives a consensus rating of pathogenic with a score of 0.53 (Min=0, Max=1), which predicts a damaging effect on gene function (PP3).

Not Met criteria codes

• BP4: The computational predictor APOGEE gives a consensus rating of pathogenic with a score of 0.53 (Min=0, Max=1), which predicts a damaging effect on gene function (PP3).
• PP1: No family member testing mentioned in cases reported to date.
• PM6: No family member testing mentioned in cases reported to date.
• PM5: No other changes at this position known to be associated with mitochondrial disease.
• PS1: No other changes at this position known to be associated with mitochondrial disease.
• PS3: No functional validation performed to date.
• PS2: No family member testing mentioned in cases reported to date.