M-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
Consequence
missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 10 ACMG points.
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 | |||
| TRNR | unassigned_transcript_4809 | c.-208G>A | upstream_gene_variant | |||||
| COX3 | unassigned_transcript_4806 | c.*207G>A | downstream_gene_variant | |||||
| TRNG | unassigned_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
Mitomap
ClinVar
Submissions by phenotype
Leigh syndrome Pathogenic:2Other:1
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variant in MTND3 gene is interpretated to be a Pathogenic variant based on the modified ACMG guidelines (unpublished).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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Mitochondrial complex 1 deficiency, mitochondrial type 1 Pathogenic:2
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. -
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not specified Pathogenic:1
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Leber optic atrophy and dystonia Pathogenic:1
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Mitochondrial disease Pathogenic:1
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
Variant confirmed as disease-causing by referring clinical team -
See cases Pathogenic:1
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not provided Pathogenic:1
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
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at