ClinVar Miner

Submissions for variant m.3733G>A

dbSNP: rs199476125
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel, ClinGen RCV002221475 SCV002498787 uncertain significance Mitochondrial disease 2022-03-24 reviewed by expert panel curation 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.
Mendelics RCV000010389 SCV002517666 pathogenic Leber optic atrophy 2022-05-04 criteria provided, single submitter clinical testing
OMIM RCV000010389 SCV000030615 pathogenic Leber optic atrophy 2004-11-01 no assertion criteria provided literature only
GeneReviews RCV000010389 SCV000086635 not provided Leber optic atrophy no assertion provided literature only This mitochondrial DNA variant affects function. It hase been identified in at least two independent LHON pedigrees and segregates with affected disease status.

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