rs121434462
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2PP3PP5_Very_Strong
The ENST00000387456.1(MT-TL2):n.50G>A variant causes a non coding transcript exon change involving the alteration of a conserved nucleotide. Variant has been reported in ClinVar as Likely pathogenic (★★★).
Frequency
Mitomap GenBank:
Absent
Consequence
MT-TL2
ENST00000387456.1 non_coding_transcript_exon
ENST00000387456.1 non_coding_transcript_exon
Scores
Mitotip
Pathogenic
Clinical Significance
CPEO-/-KSS-/-possible-carotid-atherosclerosis-risk+-trend-toward-myocardial-infarction-risk
Conservation
PhyloP100: 7.34
Genes affected
MT-TL2 (HGNC:7491): (mitochondrially encoded tRNA leucine 2 (CUN))
MT-ND5 (HGNC:7461): (mitochondrially encoded NADH dehydrogenase 5) Enables NADH dehydrogenase (ubiquinone) activity. Involved in mitochondrial electron transport, NADH to ubiquinone and mitochondrial respiratory chain complex I assembly. Part of mitochondrial respiratory chain complex I. Implicated in Leber hereditary optic neuropathy; Leigh disease; and MELAS syndrome. [provided by Alliance of Genome Resources, Apr 2022]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 11 ACMG points.
PM2
?
No frequency data in Mitomap. Probably very rare.
PP3
?
Mitotip and hmtvar scores support pathogenic criterium.
PP5
?
Variant M-12315-G-A is Pathogenic according to our data. Variant chrM-12315-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 9586.Status of the report is reviewed_by_expert_panel, 3 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TRNL2 | TRNL2.1 use as main transcript | n.50G>A | non_coding_transcript_exon_variant | 1/1 | |||
TRNS2 | TRNS2.1 use as main transcript | downstream_gene_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MT-TL2 | ENST00000387456.1 | n.50G>A | non_coding_transcript_exon_variant | 1/1 | |||||
MT-ND5 | ENST00000361567.2 | upstream_gene_variant | P1 | ||||||
MT-TS2 | ENST00000387449.1 | downstream_gene_variant |
Frequencies
GnomAD4 exome Cov.: 0
GnomAD4 exome
Cov.:
0
We have no GnomAD4 genomes data on this position. Probably position not covered by the project.
Mitomap
CPEO-/-KSS-/-possible-carotid-atherosclerosis-risk+-trend-toward-myocardial-infarction-risk
ClinVar
Significance: Likely pathogenic
Submissions summary: Pathogenic:3
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
Mitochondrial disease Pathogenic:1
Likely pathogenic, reviewed by expert panel | curation | ClinGen Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel, ClinGen | Nov 30, 2022 | The m.12315G>A variant in MT-TL2 has been reported in five affected and unrelated individuals from five families (PMIDs: one subject is reported in three different publications – 8923013, 9361028, 10332036; other subjects are reported in 12398839, 19718780, 18977334, 21819490; PS4_moderate). Age of onset ranged from childhood to adulthood (30s) and features included chronic progressive external ophthalmoplegia (CPEO), myopathy, pigmentary retinopathy, and sensorineural hearing loss. Muscle biopsies showed ragged red fibers, COX-deficiency, and reduced respiratory chain enzyme activities. Heteroplasmy levels ranged from 62-94% in muscle, from undetectable to 17% in blood, and were absent when assessed in other tissues. This variant occurred de novo in one individual (variant absent in blood, urine, and hair from healthy mother; PM6_supporting, PMID: 12398839). There were no similarly affected family members and no reports of transmission within a family to consider for evidence of segregation. This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). Single fiber testing was performed in two separate instances. This was first reported in 1996 (PMID: 8923013) and showed higher levels of the variant in fibers with no detectable COX activity (95 ± 1%, range 93–98%) than in apparently normal fibers (54 ± 33%, range 11 to 90%). Single fiber studies were again performed on a different subject in 2002 (PMID: 12398839) and revealed higher levels of the variant in COX-negative fibers (N=7, 75.34 ± 5.19% heteroplasmy, range 67.01–81.86%) than in COX-positive fibers (N=6, 32.20 ± 9.05% heteroplasmy, range 16.29–34.93%; PS3_supporting). The computational predictor MitoTIP suggests this variant is pathogenic (82.2 percentile) and HmtVAR predicts it to be pathogenic score of 0.85 (PP3). In summary, this variant meets criteria to be classified as likely pathogenic 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 November 30, 2022. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS4_moderate, PM6_supporting, PM2_supporting, PS3_supporting, PP3. - |
Juvenile myopathy, encephalopathy, lactic acidosis AND stroke Pathogenic:1
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.12315G>A variant in MT-TL2 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 encephalomyopathy Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Nov 01, 1996 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
Mitotip
Pathogenic
Hmtvar
Pathogenic
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at