M-8344-A-G
Variant summary
Our verdict is Pathogenic. The variant received 8 ACMG points: 8P and 0B. PS4PS3_SupportingPP1_ModeratePP3
This summary comes from the ClinGen Evidence Repository: The m.8344A>G variant in MT-TK was reviewed by the Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel as part of the variant pilot for mitochondrial DNA variant specifications (McCormick et al., 2020; PMID:32906214). This variant has been reported in >16 individuals with primary mitochondrial disease with variable features. While this variant is classically associated with the mitochondrial disease clinical syndrome MERRF (myoclonic epilepsy with ragged red fibers), affected individuals can have any number of features including but not limited to ataxia, myoclonus, seizures, Leigh syndrome, muscle weakness, exercise intolerance, sensorineural hearing loss, neuropathy, and lipomas, with onset ranging from childhood to adulthood (PS4; PMIDs: 2112427, 1910259, 23635963). This variant heteroplasmy level segregated with severity in >10 family members from >10 families (PP1_moderate; PMIDs: 2112427, 23635963). The computational predictor MitoTIP suggests this variant impacts the function of this tRNA, as does HmtVar with a score of 0.90 (PP3). Cybrid studies supported the functional impact of this variant including a deficiency seen in patient cell line that was transferred to cybrids with a high mutant load and study was reproducible (PS3_supporting; PMIDs: 1848674, 7739567). In summary, this variant meets criteria to be classified as pathogenic for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel as of August 20, 2020. Mitochondrial DNA-specific ACMG/AMP criteria applied: PS4, PS3_supporting, PP1_moderate, PP3. LINK:https://erepo.genome.network/evrepo/ui/classification/CA254836/MONDO:0044970/014
Frequency
Consequence
unassigned_transcript_4803 missense
Scores
Clinical Significance
Conservation
Publications
- mitochondrial diseaseInheritance: Mitochondrial Classification: DEFINITIVE Submitted by: ClinGen
- cytochrome-c oxidase deficiency diseaseInheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
- MELAS syndromeInheritance: Mitochondrial Classification: SUPPORTIVE Submitted by: Orphanet
- Leigh syndromeInheritance: Mitochondrial Classification: LIMITED Submitted by: ClinGen
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ACMG classification
Our verdict: Pathogenic. The variant received 8 ACMG points.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| TRNK | unassigned_transcript_4803 | c.50A>G | p.Asn17Ser | missense_variant | Exon 1 of 1 | |||
| ATP6 | unassigned_transcript_4805 | c.-183A>G | upstream_gene_variant | |||||
| ATP8 | unassigned_transcript_4804 | c.-22A>G | upstream_gene_variant | |||||
| COX2 | unassigned_transcript_4802 | c.*75A>G | downstream_gene_variant |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| MT-TK | ENST00000387421.1 | n.50A>G | non_coding_transcript_exon_variant | Exon 1 of 1 | 6 | |||||
| MT-ATP6 | ENST00000361899.2 | c.-183A>G | upstream_gene_variant | 6 | ENSP00000354632.2 | |||||
| MT-ATP8 | ENST00000361851.1 | c.-22A>G | upstream_gene_variant | 6 | ENSP00000355265.1 | |||||
| MT-CO2 | ENST00000361739.1 | c.*75A>G | downstream_gene_variant | 6 | ENSP00000354876.1 |
Frequencies
Mitomap
ClinVar
Submissions by phenotype
MERRF syndrome Pathogenic:5Other:1
This is a known pathogenic variant that accounts for about 80% of individuals with MERRF.
The variant is observed at an extremely low frequency in the gnomAD v4.1.0 dataset (heteroplasmic allele frequency: 0.011%). Predicted Consequence/Location: Mitochondrial variant Functional studies provide supporting evidence of the variant having a damaging effect on the gene or gene product (PMID: 1848674, 7739567). The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 1910259, 2112427, 23635963). The variant has been reported to co-segregate with the disease in at least 3 similarly affected relatives/individuals in the same family or similarly affected unrelated family (PMID: 2112427, 23635963). The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (3billion dataset/ClinVar ID: VCV000009579). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Most common pathogenic variant; identified in more than 80% of persons w/MERRF
Criteria applied: PS4_VSTR,PP1_MOD,PS3_SUP,PP3
not provided Pathogenic:4
Mitochondrial disease Pathogenic:2
The m.8344A>G variant in MT-TK was reviewed by the Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel as part of the variant pilot for mitochondrial DNA variant specifications (McCormick et al., 2020; PMID: 32906214). This variant has been reported in >16 individuals with primary mitochondrial disease with variable features. While this variant is classically associated with the mitochondrial disease clinical syndrome MERRF (myoclonic epilepsy with ragged red fibers), affected individuals can have any number of features including but not limited to ataxia, myoclonus, seizures, Leigh syndrome, muscle weakness, exercise intolerance, sensorineural hearing loss, neuropathy, and lipomas, with onset ranging from childhood to adulthood (PS4; PMIDs: 2112427, 1910259, 23635963). This variant heteroplasmy level segregated with severity in >10 family members from >10 families (PP1_moderate; PMIDs: 2112427, 23635963). The computational predictor MitoTIP suggests this variant impacts the function of this tRNA, as does HmtVar with a score of 0.90 (PP3). Cybrid studies supported the functional impact of this variant including a deficiency seen in patient cell line that was transferred to cybrids with a high mutant load and study was reproducible (PS3_supporting; PMIDs: 1848674, 7739567). In summary, this variant meets criteria to be classified as pathogenic for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel as of August 20, 2020. Mitochondrial DNA-specific ACMG/AMP criteria applied: PS4, PS3_supporting, PP1_moderate, PP3.
MELAS syndrome Pathogenic:2
The NC_012920.1:m.8344A>G variant in MT-TK 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
Leigh syndrome Pathogenic:1Other:1
Complex hereditary spastic paraplegia Pathogenic:1
Variant confirmed as disease-causing by referring clinical team
MT-TK-related disorder Pathogenic:1
MT-TK-related mitochondrial disorder Pathogenic:1
The variant m.8344A>G in the MT-TK gene is reported as pathogenic for MERRF and other mitochondrial diseases in MITOMAP database. This variant is reported as pathogenic for MERRF syndrome, Leigh syndrome and mitochondrial disorder in ClinVar (Variation ID: 9579). The variant is reported with a frequency of 0.008% in the current dataset of full-length mitochondrial sequences from GenBank. The variant m.8344A>G is the most common variant identified in patients with MERRF (myoclonic epilepsy with ragged red fibers), accounting for about 80% of cases (Velez-Bartolomei et al., 2021, PMID: 20301693). However, this variant has also been reported in patients with other forms of mitochondrial diseases, such as Leigh syndrome (Tsao et al., 2003, PMID: 12661941), cavitating leukoencephalopathy (Biancheri et al., 2010, PMID: 20581069) and Parkinson disease (OMIM * 590060). The variant has also been reported as pathogenic by Wong and colleagues in the recent article on mitochondrial tRNA variant interpretation (PMID: 31965079).
Parkinson disease, mitochondrial Pathogenic:1
Thrombocythemia 2 Pathogenic:1
This MT-TK variant (rs118192098) is rare (<0.1%) in a large population dataset (gnomAD: 6/56419 total alleles; AF(het)=0.0106%); AF(hom)=0.00%) and has been reported in ClinVar and Mitomap. It has been reviewed by an ClinGen expert panel and classified as pathogenic for primary mitochondrial disease. m.8344A>G has been reported in multiple unrelated individuals with primary mitochondrial disease showing variable phenotypic features and accounts for approximately 80% of individuals with MERRF. Independent experimental studies using cybrid cell lines with mtDNAs containing this variant demonstrated a functional impact at high mutation loads (heteroplasmy) compared to wild-type mtDNAs. We consider this variant to be pathogenic for MT-TK-related mitochondrial disorder.
Computational scores
Source: