rs199474660
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PP5_Very_Strong
Variant has been reported in ClinVar as Likely pathogenic (★★★).
Frequency
Consequence
missense, splice_region
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 |
|---|---|---|---|---|---|---|---|---|
| TRNL1 | unassigned_transcript_4788 | c.74C>T | p.Thr25Ile | missense_variant, splice_region_variant | Exon 1 of 1 | |||
| ND1 | unassigned_transcript_4789 | c.-4C>T | upstream_gene_variant | |||||
| RNR2 | unassigned_transcript_4787 | n.*74C>T | 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
MELAS syndrome Pathogenic:2
The NC_012920.1:m.3303C>T variant in MT-TL1 gene is interpreted to be a Pathogenic variant based on the modified ACMG guidelines (unpublished).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: PS5, PM7, PM9, PM10 -
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Mitochondrial disease Pathogenic:1
The m.3303C>T variant in MT-TL1 has been reported in at least 16 unrelated individuals with primary mitochondrial disease (PS4; 13 individuals were reported in the medical literature, PMIDs: 23847141, 10431114, 32167396, 11768589, 33013660, 20226758, 23258140, 7906985, 31965079; an additional three cases were known to members of this Expert Panel). Many affected individuals had hypertrophic cardiomyopathy and/or skeletal myopathy, as well as exercise intolerance, muscle weakness, lactic acidosis, and failure to thrive. Age of onset varied from infancy to adulthood. Heteroplasmy levels in affected individuals ranged from 58-97% in muscle, 20-80% in blood, and, in one case, was almost homoplasmic in fibroblasts. There are no de novo occurrences of this variant to our knowledge. 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; PMID: 10431114, also seen in cases known to Expert Panel members). Of note, there is a report of this variant in individuals with premature ovarian insufficiency (POI, PMID: 30404982), however this Expert Panel agreed this presentation, when isolated, is not known to be associated with mitochondrial DNA etiologies and it is not clear other organ systems were or were not screened in these cases. Therefore, these cases were not considered as supporting evidence for this variant classification. There is one occurrence in population databases as one individual in the Helix dataset had this variant present at heteroplasmy. Although there is one occurrence, the frequency is still low (PM2_supporting). The computational predictor MitoTIP suggests this variant is pathogenic (92.7 percentile) and HmtVAR predicts it to be pathogenic score of 0.65 (PP3). Single fiber testing (PMID: 11271374) showed higher levels of the variant in ragged red fibers that were COX-negative (42.4±7.0%) and in ragged red fibers that were COX-positive (58.2±5.8%), and this was significantly higher than levels of the variant in normal appearing fibers (10.7±6.3%; PS3_supporting). Of note, cybrid studies are reported however the generated cybrids include other mitochondrial DNA variants precluding consideration as evidence of pathogenicity of this variant only (PMID: 30404982). In summary, this variant meets criteria to be classified as likely pathogenic for primary mitochondrial disease inherited in a mitochondrial manner. We note, however, that some members of this Expert Panel elected to modify the classification to pathogenic given the extent of cases from different ethnic backgrounds that have been reported with overlapping phenotypes that is further supported by the evidence outlined above. The experts were almost evenly divided on the final classification as five experts voted to keep the classification as likely pathogenic and four voted for pathogenic. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on January 9, 2023. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS4, PP1_moderate, PM2_supporting, PP3, PS3_supporting. -
MITOCHONDRIAL CARDIOMYOPATHY WITH OR WITHOUT SKELETAL MYOPATHY Pathogenic:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at