The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]
  • There was no gene found in the curated document received from the VCI/VCEP
  • The variant label for this record ("m.3733G>A") does not appear to be in HGVS format
  • No CSPEC related information was provided by the message!
  • No CSPEC computed assertion could be determined for this classification!

  • See Evidence submitted by expert panel for details.

Variant: m.3733G>A

CA340950

9736 (ClinVar)

Gene: N/A
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:c.427G>A

Uncertain Significance

Met criteria codes 3
PP3 PS4_Moderate PM2_Supporting
Not Met criteria codes 7
PP1 PM5 PS1 PS2 PS3 PM6 BP4

Evidence Links 0

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
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
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).
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).
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.
Not Met criteria codes
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).
PM5
m.3733G>A (p.E143Q) has been reported in one individual (PMID: 22879922) however this variant is not definitively pathogenic.
PS1
No other variants resulting in the same amino acid change have been reported.
PS2
There are no reports of de novo occurrences.
PS3
No functional validation has been performed to date.
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).
Curation History
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