rs397515612
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3
The ENST00000361390.2(MT-ND1):c.70G>A(p.Glu24Lys) variant causes a missense change. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★★).
Frequency
Mitomap GenBank:
Absent
Consequence
MT-ND1
ENST00000361390.2 missense
ENST00000361390.2 missense
Scores
Apogee2
Pathogenic
Clinical Significance
LHON-MELAS-overlap
Conservation
PhyloP100: 6.32
Genes affected
MT-ND1 (HGNC:7455): (mitochondrially encoded NADH dehydrogenase 1) Enables NADH dehydrogenase (ubiquinone) activity. Involved in mitochondrial electron transport, NADH to ubiquinone and mitochondrial respiratory chain complex I assembly. Located in mitochondrial membrane. Part of mitochondrial respiratory chain complex I. Implicated in several diseases, including MELAS syndrome; neurodegenerative disease (multiple); optic nerve disease (multiple); toxic shock syndrome; and type 2 diabetes mellitus. Biomarker of Alzheimer's disease; Parkinson's disease; and multiple sclerosis. [provided by Alliance of Genome Resources, Apr 2022]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 3 ACMG points.
PM2
?
No frequency data in Mitomap. Probably very rare.
PP3
?
Apogee2 supports a deletorius effect, 0.9352679 >= 0.5 .
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.70G>A | p.Glu24Lys | missense_variant | 1/1 | P1 |
Frequencies
GnomAD4 exome Cov.: 0
GnomAD4 exome
Cov.:
0
We have no GnomAD4 genomes data on this position. Probably position not covered by the project.
Mitomap
LHON-MELAS-overlap
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1Other:1
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
Mitochondrial disease Uncertain:1
Uncertain significance, reviewed by expert panel | curation | ClinGen Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel, ClinGen | Jun 30, 2022 | The m.3376G>A (p.E24K) variant in MT-ND1 has been reported in one individual to date with primary mitochondrial disease. This individual had features in the MELAS/LHON spectrums and harbored the variant at 98% heteroplasmy in muscle, 18% in blood, and 67% in urine. This does not meet criteria for PS4_supporting which requires at least two unrelated affected individuals. This variant was de novo in the single reported case, as the proband's mother and siblings did not have the variant in blood or urine via PCR-RFLP (PS2_supporting; PMID: 15657614). There are no large families reported in the medical literature to consider for evidence of segregation. This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). The computational predictor APOGEE gives a consensus rating of neutral with a borderline pathogenicity predictor score, 0.5 (Min=0, Max=1), evidence that does not predict a damaging effect on gene function (BP4). There are no cybrids or single fiber studies reported on this variant. 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 February 14, 2022. Mitochondrial DNA-specific ACMG/AMP criteria (PMID: 32906214): PS2_supporting, PM2_supporting, BP4. - |
Leber optic atrophy Other:1
not provided, no classification provided | literature only | GeneReviews | - | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
Apogee2
Pathogenic
Hmtvar
Pathogenic
AlphaMissense
Pathogenic
BayesDel_addAF
Uncertain
D
DEOGEN2
Uncertain
T
LIST_S2
Uncertain
D
MutationAssessor
Pathogenic
H
MutationTaster
Benign
A
PROVEAN
Uncertain
D
Sift4G
Pathogenic
D
GERP RS
Varity_R
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at