M-3243-A-T
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2_SupportingPS3_ModeratePP3PS4_ModeratePM5_Supporting
This summary comes from the ClinGen Evidence Repository: The m.3243A>T variant in MT-TL1 has been reported in eight unrelated probands with primary mitochondrial disease. Features in affected individuals include mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) and chronic progressive external ophthalmoplegia (CPEO), as well as myoclonic epilepsy, exercise intolerance with rhabdomyolysis, cataracts, sensorineural hearing loss, diabetes, peripheral neuropathy, and ataxia (PMIDs: 9168904, 18203188, 20471262, 23220830, 30210801, 33924034, 25504047; PS4_moderate). In all individuals, the variant was present at heteroplasmy, ranging from 69-99% in muscle and 13-50% in blood. Age of onset varied from six to 29 years old. There are no large families reported in the medical literature to consider for evidence of segregation. There are no de novo occurrences of this variant reported to our knowledge. The m.3243A>T variant is absent in the GenBank dataset and gnomAD3.1.2. There is one heteroplasmic occurrence in 195,893 sequences in the Helix database, however the overall frequency is still low (PM2_supporting). The computational predictor MitoTIP suggests this variant is pathogenic, scoring in the 58.8 percentile, and HmtVAR also predicts it to be pathogenic with a score of 0.8 (PP3). The m.3243A>T variant is at the same nucleotide position as a previously established pathogenic variant (m. 3243A>G; PM5_supporting). Several different functional studies have been performed on this variant that support its pathogenicity and show independent deleterious effects of the variant, including generation of cybrids, single fiber testing, and aminoacylation assays (PS3_moderate). Cybrids with high levels of this variant, when compared to wild type, showed lower oxygen consumption, higher glucose consumption and lactate production, increased motility and migration capacities associated with specific glycosylation patterns, lower growth rate, and altered cellular processes (PMIDs: 25504047, 32273537). Single fiber testing showed higher levels of the variant in COX-deficient fibers (95.8 ± 0.7%, n=9) than in COX-positive fibers (44.3 ± 8.8%, n=9; p < 0.001; PMID:20471262). Structural and aminoacylation studies of in-vitro transcribed human tRNALeu(UUR) showed that the m.3243A>T variant was associated with a 300-fold loss of aminoacylation efficiency (PMID:12729737). In summary, this variant meets criteria to be classified as likely pathogenic for primary mitochondrial disease inherited in a mitochondrial manner. We note that one expert on this panel felt pathogenic was a more appropriate classification given the functional evidence of impact however the majority agreed with likely pathogenic. 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 (PMID:32906214): PS4_moderate, PM2_supporting, PP3, PM5_supporting, PS3_moderate. LINK:https://erepo.genome.network/evrepo/ui/classification/CA913168968/MONDO:0044970/014
Frequency
Consequence
ENST00000386347.1 non_coding_transcript_exon
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
|---|---|---|---|---|---|---|---|
| TRNL1 | TRNL1.1 use as main transcript | n.14A>T | non_coding_transcript_exon_variant | 1/1 | |||
| RNR2 | RNR2.1 use as main transcript | downstream_gene_variant |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| MT-TL1 | ENST00000386347.1 | n.14A>T | non_coding_transcript_exon_variant | 1/1 | |||||
| MT-RNR2 | ENST00000387347.2 | downstream_gene_variant |
Frequencies
GnomAD4 exome Cov.: 0
Mitomap
ClinVar
Submissions by phenotype
Juvenile myopathy, encephalopathy, lactic acidosis AND stroke Pathogenic:2Other:1
| not provided, no classification provided | phenotyping only | GenomeConnect, ClinGen | - | Variant classified as Pathogenic and reported on 08-31-2015 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. - |
| 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.3243A>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: PS3, PS5, PM5, PP3 - |
| Pathogenic, criteria provided, single submitter | clinical testing | Mendelics | May 04, 2022 | - - |
Mitochondrial disease Pathogenic:1
| Likely pathogenic, reviewed by expert panel | curation | ClinGen Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel, ClinGen | Oct 10, 2022 | The m.3243A>T variant in MT-TL1 has been reported in eight unrelated probands with primary mitochondrial disease. Features in affected individuals include mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) and chronic progressive external ophthalmoplegia (CPEO), as well as myoclonic epilepsy, exercise intolerance with rhabdomyolysis, cataracts, sensorineural hearing loss, diabetes, peripheral neuropathy, and ataxia (PMIDs: 9168904, 18203188, 20471262, 23220830, 30210801, 33924034, 25504047; PS4_moderate). In all individuals, the variant was present at heteroplasmy, ranging from 69-99% in muscle and 13-50% in blood. Age of onset varied from six to 29 years old. There are no large families reported in the medical literature to consider for evidence of segregation. There are no de novo occurrences of this variant reported to our knowledge. The m.3243A>T variant is absent in the GenBank dataset and gnomAD3.1.2. There is one heteroplasmic occurrence in 195,893 sequences in the Helix database, however the overall frequency is still low (PM2_supporting). The computational predictor MitoTIP suggests this variant is pathogenic, scoring in the 58.8 percentile, and HmtVAR also predicts it to be pathogenic with a score of 0.8 (PP3). The m.3243A>T variant is at the same nucleotide position as a previously established pathogenic variant (m. 3243A>G; PM5_supporting). Several different functional studies have been performed on this variant that support its pathogenicity and show independent deleterious effects of the variant, including generation of cybrids, single fiber testing, and aminoacylation assays (PS3_moderate). Cybrids with high levels of this variant, when compared to wild type, showed lower oxygen consumption, higher glucose consumption and lactate production, increased motility and migration capacities associated with specific glycosylation patterns, lower growth rate, and altered cellular processes (PMIDs: 25504047, 32273537). Single fiber testing showed higher levels of the variant in COX-deficient fibers (95.8 ± 0.7%, n=9) than in COX-positive fibers (44.3 ± 8.8%, n=9; p < 0.001; PMID: 20471262). Structural and aminoacylation studies of in-vitro transcribed human tRNALeu(UUR) showed that the m.3243A>T variant was associated with a 300-fold loss of aminoacylation efficiency (PMID: 12729737). In summary, this variant meets criteria to be classified as likely pathogenic for primary mitochondrial disease inherited in a mitochondrial manner. We note that one expert on this panel felt pathogenic was a more appropriate classification given the functional evidence of impact however the majority agreed with likely pathogenic. 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 (PMID: 32906214): PS4_moderate, PM2_supporting, PP3, PM5_supporting, PS3_moderate. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at