chrM-10197-G-A

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

Scores

Apogee2
Pathogenic
0.84

Clinical Significance

Pathogenic reviewed by expert panel P:11O:1
Leigh-Disease-/-Dystonia-/-Stroke-/-LDYT,Leigh-Disease

Conservation

PhyloP100: 4.69
Variant links:
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]
TRNR (HGNC:7496): (mitochondrially encoded tRNA arginine)
COX3 (HGNC:7422): (mitochondrially encoded cytochrome c oxidase III) Predicted to enable electron transfer activity and oxidoreduction-driven active transmembrane transporter activity. Involved in respiratory chain complex IV assembly. Part of respiratory chain complex IV. Implicated in MELAS syndrome. [provided by Alliance of Genome Resources, Apr 2022]
TRNG (HGNC:7486): (mitochondrially encoded tRNA glycine)

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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
ND3unassigned_transcript_4808 c.139G>A p.Ala47Thr missense_variant Exon 1 of 1
TRNRunassigned_transcript_4809 c.-208G>A upstream_gene_variant
COX3unassigned_transcript_4806 c.*207G>A downstream_gene_variant
TRNGunassigned_transcript_4807 c.*139G>A downstream_gene_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt

Frequencies

GnomAD4 exome
Cov.:
0
We have no GnomAD4 genomes data on this position. Probably position not covered by the project.
Alfa
AF:
0.000223
Hom.:
0

Mitomap

Leigh-Disease-/-Dystonia-/-Stroke-/-LDYT,Leigh-Disease

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:11Other:1
Revision: reviewed by expert panel
LINK: link

Submissions by phenotype

Leigh syndrome Pathogenic:2Other:1
Oct 17, 2019
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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 -

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Pediatric Department, Xiangya Hospital, Central South University
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

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GeneReviews
Significance: not provided
Review Status: no classification provided
Collection Method: literature only

- -

Mitochondrial complex 1 deficiency, mitochondrial type 1 Pathogenic:2
Feb 14, 2024
3billion
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The variant is not observed in the gnomAD v3.1.2 dataset. Predicted Consequence/Location: Missense variant In silico tool predictions suggest damaging effect of the variant on gene or gene product (APOGEE : 0.88 >= 0.5). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (3billion dataset/ClinVar ID: VCV000009715). The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 15372108, 17152068, 17413873, 18977334, 19458970, 20818383, 20972245, 24708134, 30128709, 30199507, 30776730, 32045392). The variant has been previously reported as assumed (i.e. paternity and maternity not confirmed) de novo in at least two similarly affected unrelated individuals (PMID: 17413873, 24708134). The variant has been reported to co-segregate with the disease in at least 5 similarly affected relatives/individuals in the same family or similarly affected unrelated families (PMID: 17152068, 17413873, 30128709, 30776730). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

Oct 01, 2009
OMIM
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: literature only

- -

not specified Pathogenic:1
Sep 22, 2022
Institute for Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Leber optic atrophy and dystonia Pathogenic:1
Oct 01, 2009
OMIM
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: literature only

- -

Mitochondrial disease Pathogenic:1
Jul 25, 2022
ClinGen Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel, ClinGen
Significance: Pathogenic
Review Status: reviewed by expert panel
Collection Method: curation

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. -

Mitochondrial myopathy, episodic, with optic atrophy and reversible leukoencephalopathy Pathogenic:1
Jun 01, 2022
Solve-RD Consortium
Significance: Likely pathogenic
Review Status: no assertion criteria provided
Collection Method: provider interpretation

Variant confirmed as disease-causing by referring clinical team -

See cases Pathogenic:1
Jun 15, 2023
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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not provided Pathogenic:1
Sep 29, 2017
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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 DNA-Associated Leigh Syndrome and NARP Pathogenic:1
May 04, 2022
Mendelics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
Apogee2
Pathogenic
0.84
Hmtvar
Pathogenic
0.79
AlphaMissense
Benign
0.25
BayesDel_addAF
Benign
-0.22
T
DEOGEN2
Uncertain
0.53
D
LIST_S2
Benign
0.82
T
MutationAssessor
Uncertain
2.0
M
PROVEAN
Uncertain
-3.5
D
Sift
Uncertain
0.010
D
Sift4G
Pathogenic
0.0
D
GERP RS
5.1
Varity_R
0.22

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs267606891; hg19: chrM-10198; API