M-4308-G-A
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PS4_SupportingPM2_SupportingPM6_SupportingPP3
This summary comes from the ClinGen Evidence Repository: The m.4308G>A variant in MT-TI has been reported in two unrelated individuals with primary mitochondrial disease with onset ranging from the first decade to third decade of life and features include bilateral ptosis, chronic progressive external ophthalmoplegia (CPEO), exercise intolerance, decreased BMI, and hyperCKemia. Muscle biopsy showed paracrystalline inclusions, ragged red fibers, COX negative fibers, and respiratory chain deficiencies across complexes I, III, and IV. In both cases, the variant was undetectable in blood when the individuals were tested in their 30s and 50s. The variant was heteroplasmic in muscle, however the exact heteroplasmy level was only reported in one of these cases at 47%. Neither case had any positive family history (PS4_supporting; PMIDs: 20884012; 21292040). This variant occurred de novo in one individual (absent in blood and muscle from mother via RFLP; PM6_supporting, PMID:21292040). 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 MitoTIP suggests this variant is pathogenic (82.1 percentile) and HmtVAR predicts it to be pathogenic score of 0.55 (PP3). There are no cybrids, single fiber studies, or other functional assays 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 ClinGen Mitochondrial Disease Variant Curation Expert Panel on October 10, 2022. Mitochondrial DNA-specific ACMG/AMP criteria applied: PS4_supporting, PM2_supporting, PP3, PM6_supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA913177679/MONDO:0044970/014
Frequency
Consequence
ENST00000387365.1 non_coding_transcript_exon
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 4 ACMG points.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| TRNI | TRNI.1 use as main transcript | n.46G>A | non_coding_transcript_exon_variant | 1/1 | ||||
| TRNQ | TRNQ.1 use as main transcript | downstream_gene_variant |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| MT-TI | ENST00000387365.1 | n.46G>A | non_coding_transcript_exon_variant | 1/1 | ||||||
| MT-ND1 | ENST00000361390.2 | downstream_gene_variant | ENSP00000354687 | P1 | ||||||
| MT-TQ | ENST00000387372.1 | downstream_gene_variant |
Frequencies
GnomAD4 exome Cov.: 0
Mitomap
ClinVar
Submissions by phenotype
Juvenile myopathy, encephalopathy, lactic acidosis AND stroke Pathogenic:1
| Likely pathogenic, criteria provided, single submitter | clinical testing | Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine | Jul 12, 2019 | The NC_012920.1:m.4308G>A variant in MT-TI gene is interpreted to be a Likely Pathogenic variant based on the modified ACMG guidelines (unpublished). This variant meets the following evidence codes reported in the guidelines: PM7, PM8, PM9, PM10, PP6 - |
Mitochondrial disease Uncertain:1
| Uncertain significance, reviewed by expert panel | curation | ClinGen Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel, ClinGen | Oct 10, 2022 | The m.4308G>A variant in MT-TI has been reported in two unrelated individuals with primary mitochondrial disease with onset ranging from the first decade to third decade of life and features include bilateral ptosis, chronic progressive external ophthalmoplegia (CPEO), exercise intolerance, decreased BMI, and hyperCKemia. Muscle biopsy showed paracrystalline inclusions, ragged red fibers, COX negative fibers, and respiratory chain deficiencies across complexes I, III, and IV. In both cases, the variant was undetectable in blood when the individuals were tested in their 30s and 50s. The variant was heteroplasmic in muscle, however the exact heteroplasmy level was only reported in one of these cases at 47%. Neither case had any positive family history (PS4_supporting; PMIDs: 20884012; 21292040). This variant occurred de novo in one individual (absent in blood and muscle from mother via RFLP; PM6_supporting, PMID: 21292040). 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 MitoTIP suggests this variant is pathogenic (82.1 percentile) and HmtVAR predicts it to be pathogenic score of 0.55 (PP3). There are no cybrids, single fiber studies, or other functional assays 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 ClinGen Mitochondrial Disease Variant Curation Expert Panel on October 10, 2022. Mitochondrial DNA-specific ACMG/AMP criteria applied: PS4_supporting, PM2_supporting, PP3, PM6_supporting. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at