M-4298-G-A
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP5_Strong
Variant has been reported in ClinVar as Uncertain significance (★★★).
Frequency
Consequence
synonymous
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| TRNI | unassigned_transcript_4790 | c.36G>A | p.Glu12Glu | synonymous_variant | Exon 1 of 1 | |||
| ND2 | unassigned_transcript_4793 | c.-172G>A | upstream_gene_variant | |||||
| TRNM | unassigned_transcript_4792 | c.-104G>A | upstream_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
MELAS syndrome Pathogenic:1
The NC_012920.1:m.4298G>A variant in MT-TI gene is interpreted to be a Pathogenic variant based on the modified ACMG guidelines (unpublished). This variant meets the following evidence codes reported in the guidelines: PS3, PS5, PM7 -
Mitochondrial disease Uncertain:1
The m.4298G>A variant in MT-TI has been reported in two unrelated adults with primary mitochondrial disease. Chronic progressive external ophthalmoplegia (CPEO) and multiple sclerosis (MS) were seen in one individual (PMID: 9473477) and the second individual had rhabdomyolysis, myoglobinuria, and myalgia after fasting or exercise in addition to muscle weakness and unstable gait (PMID: 16120360). This variant was seen in varying degrees of heteroplasmy in these individuals in muscle, urine, and hair roots by PCR/RFLP, but was not observed in blood (PS4_supporting). Family member testing was performed in one case and the variant was undetectable in the proband’s mother’s blood, however the variant was also undetectable in the proband’s blood precluding confirmation of a de novo occurrence (PMID: 16120360). There are no large families reported in the medical literature to consider for evidence of segregation. The computational predictor MitoTIP suggests this variant is pathogenic, scoring in the 63.5 percentile; HmtVAR also predicts it to be pathogenic, scoring in the 75.0 percentile (PP3). The m.4298G>A variant is absent in the GenBank dataset, the Helix dataset, and gnomAD v3.1.2 (PM2_supporting). Single-fiber testing (PMID: 9473477) showed 78% heteroplasmy in COX-negative fibers and 27% in COX-positive fibers. Aminoacylation assays showed that the capacity for aminoacylation of tRNAs with this variant was virtually nil (<0.1%) and the observed aminoacylation deficiency was rescued by an engineered compensatory variant (PMID: 12655007). This and other results led the authors to propose that the functional defect caused by this mutation is due to fragility of the tRNA structure (PS3_supporting). In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a mitochondrial manner. We note that two experts on this panel felt likely pathogenic was a more appropriate classification given the functional evidence of impact however the majority agreed with uncertain significance. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on December 12, 2022. Mitochondrial DNA-specific ACMG/AMP criteria applied: PS4_supporting, PS3_supporting, PP3, PM2_supporting. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at