rs397515508
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PP3PM2_SupportingPS4_Supporting
This summary comes from the ClinGen Evidence Repository: 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. LINK:https://erepo.genome.network/evrepo/ui/classification/CA344828/MONDO:0044970/014
Frequency
Consequence
ENST00000361390.2 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Uncertain_significance. Variant got 3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MT-ND1 | ENST00000361390.2 | c.394G>A | p.Ala132Thr | missense_variant | 1/1 | P1 |
Frequencies
GnomAD4 exome Cov.: 0
Mitomap
ClinVar
Submissions by phenotype
Abnormal electroretinogram;C3665386:Visual loss;C3887709:Optic neuropathy Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | Centre for Mendelian Genomics, University Medical Centre Ljubljana | Mar 21, 2016 | - - |
Mitochondrial disease Uncertain:1
Uncertain significance, reviewed by expert panel | curation | ClinGen Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel, ClinGen | Mar 24, 2022 | 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. - |
Leber optic atrophy Other:1
not provided, no classification provided | literature only | GeneReviews | - | This mitochondrial DNA variant affects function. It hase been identified in at least two independent LHON pedigrees and segregates with affected disease status. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at