M-10197-G-A
Variant names:
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PP5_Very_Strong
In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★★).
Frequency
Mitomap GenBank:
Absent
Consequence
ND3
missense
missense
Scores
Apogee2
Pathogenic
Clinical Significance
Leigh-Disease-/-Dystonia-/-Stroke-/-LDYT,Leigh-Disease
Conservation
PhyloP100: 4.69
Genes affected
ND3 (HGNC:7458): (mitochondrially encoded NADH dehydrogenase 3) Enables NADH dehydrogenase (ubiquinone) activity. Involved in mitochondrial electron transport, NADH to ubiquinone. Part of mitochondrial respiratory chain complex I. Implicated in Leber hereditary optic neuropathy; Leigh disease; and Parkinson's disease. [provided by Alliance of Genome Resources, Apr 2022]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 10 ACMG points.
PM2
No frequency data in Mitomap. Probably very rare.
PP5
Variant M-10197-G-A is Pathogenic according to our data. Variant chrM-10197-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 9715.Status of the report is reviewed_by_expert_panel, 3 stars.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| ND3 | unassigned_transcript_4808 | c.139G>A | p.Ala47Thr | missense_variant | Exon 1 of 1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
|---|
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.
Alfa
AF:
Hom.:
Mitomap
Leigh-Disease-/-Dystonia-/-Stroke-/-LDYT,Leigh-Disease
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:10Other:1
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
Leigh syndrome Pathogenic:2Other:1
| Pathogenic, criteria provided, single submitter | clinical testing | Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine | Oct 17, 2019 | The NC_012920.1:m.10197G>A (YP_003024033.1:p.Ala47Thr) variant in MTND3 gene is interpretated to be a Pathogenic variant based on the modified ACMG guidelines (unpublished). This variant meets the following evidence codes: PS1, PM9, PM10, PP4, PP6 - |
| not provided, no classification provided | literature only | GeneReviews | - | - - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Pediatric Department, Xiangya Hospital, Central South University | - | - - |
not specified Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Institute for Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin | Sep 22, 2022 | - - |
Leber optic atrophy and dystonia Pathogenic:1
| Pathogenic, no assertion criteria provided | literature only | OMIM | Oct 01, 2009 | - - |
Mitochondrial myopathy, episodic, with optic atrophy and reversible leukoencephalopathy Pathogenic:1
| Likely pathogenic, no assertion criteria provided | provider interpretation | Solve-RD Consortium | Jun 01, 2022 | Variant confirmed as disease-causing by referring clinical team - |
Mitochondrial disease Pathogenic:1
| Pathogenic, reviewed by expert panel | curation | ClinGen Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel, ClinGen | Jul 25, 2022 | The m.10197G>A (p.A47T) variant in MT-ND3 has been reported in at least 22 probands with primary mitochondrial disease. Affected individuals had variable ages of onset (first months of life to childhood to adulthood). Features included Leigh syndrome, Leigh syndrome/MELAS overlap, and LHON with good visual recovery. Heteroplasmy levels were variable among tissues and affected individuals, and ranged from 10% (in an individual with LHON) to homoplasmy (in an individual with Leigh syndrome; PS4; PMIDs: 15372108, 17152068, 17413873, 18977334, 19458970, 20818383, 20972245, 24708134, 30128709, 30199507, 30776730, 32045392; two articles with no PMIDs: Pereira et al., 2019; JIEMS, 2019, Vol7: e20180003; Huang et al., 2017, J Clin Exp Ophthalmol 2017, 8:4). This variant segregated with disease in multiple affected members in multiple families and several healthy family members had lower to undetectable levels of the variant (PP1_moderate; PMIDs: 17152068, 17413873, 30128709, 30776730). This variant occurred de novo in at least three individuals (PM6_moderate, PMIDs: 24708134, 17413873; article with no PMID: Huang et al., 2017, J Clin Exp Ophthalmol 2017, 8:4). There are four occurrences of this variant in the GenBank dataset, and three of these four are not listed as patient sequences. However, upon discussion on the Expert Panel (EP) call, concern was raised that phylogenetic studies use patient samples and submit these to GenBank. This variant is absent in gnomAD v3.1.2 and in Helix dataset so the EP agreed to consider this supporting line of evidence (PM2_supporting). Cybrid studies showed a correlation between higher heteroplasmy level and lower complex I activity (PS3_supporting, PMID: 17152068). The computational predictor APOGEE gives a consensus rating of pathogenic with a score of 0.88 (Min=0, Max=1), which predicts a damaging effect on gene function (PP3). In summary, this variant meets criteria to be classified as pathogenic 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 July 25, 2022. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PM2_supporting, PP3, PP1_moderate, PS3_supporting, PM6_moderate, PS4. - |
See cases Pathogenic:1
| Likely pathogenic, criteria provided, single submitter | clinical testing | Equipe Genetique des Anomalies du Developpement, Université de Bourgogne | Jun 15, 2023 | - - |
not provided Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Sep 29, 2017 | The m.10197G>A variant (rs267606891) affects the MT-ND3 gene involved in mitochondrial complex I (CI) function, and has been identified in several patients with symptoms of Leigh disease (LD), LD-like, dystonia, and/or other symptoms associated with CI dysfunction (see link to GeneReviews below). This variant was first identified by Kirby (2004), wherein a patient harboring this variant is described as having LD-like symptoms and was shown to have reduced CI activity in cultured fibroblasts. Subsequent studies have also identified this variant in a French family affected with LS (Sarzi 2007), a Korean family with basal ganglia lesions (Chae 2007), and a single individual with LS (Valente 2009). All affected individuals studied have also been shown to have reduced CI activity in cell culture. Also, when analyzed, the degree of heteroplasmy tracks with disease severity, with asymptomatic carriers showing reduced levels of variant load compared to affected patients. Additionally, this variant is rare in MITOMAP, and is not associated with any particular haplogroup. Therefore, the m.10197G>A variant satisfies our criteria for classification as pathogenic. - |
Mitochondrial complex 1 deficiency, mitochondrial type 1 Pathogenic:1
| Pathogenic, no assertion criteria provided | literature only | OMIM | Oct 01, 2009 | - - |
Mitochondrial DNA-Associated Leigh Syndrome and NARP Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Mendelics | May 04, 2022 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
Apogee2
Pathogenic
Hmtvar
Pathogenic
AlphaMissense
Benign
BayesDel_addAF
Benign
T
DEOGEN2
Uncertain
D
LIST_S2
Benign
T
MutationAssessor
Uncertain
M
PROVEAN
Uncertain
D
Sift
Uncertain
D
Sift4G
Pathogenic
D
GERP RS
Varity_R
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at