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rs118192098

Variant summary

Our verdict is Pathogenic. Variant got 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

Mitomap GenBank:
Absent

Consequence

MT-TK
ENST00000387421.1 non_coding_transcript_exon

Scores

Mitotip
Uncertain
11

Clinical Significance

Pathogenic reviewed by expert panel P:15O:2
MERRF|-Other---LD-/-depressive-mood-disorder-/-leukoencephalopathy-/-HiCM-/-lipomas

Conservation

PhyloP100: -2.79
Variant links:
Genes affected
MT-TK (HGNC:7489): (mitochondrially encoded tRNA lysine)
MT-ATP8 (HGNC:7415): (mitochondrially encoded ATP synthase 8) Contributes to proton-transporting ATP synthase activity, rotational mechanism. Involved in mitochondrial ATP synthesis coupled proton transport. Part of mitochondrial proton-transporting ATP synthase complex. Implicated in multiple sclerosis and urinary bladder cancer. [provided by Alliance of Genome Resources, Apr 2022]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 8 ACMG points.

PS3
PS4
PP1
PP3

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
TRNKTRNK.1 use as main transcriptn.50A>G non_coding_transcript_exon_variant 1/1
ATP8ATP8.1 use as main transcript upstream_gene_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
MT-TKENST00000387421.1 linkuse as main transcriptn.50A>G non_coding_transcript_exon_variant 1/1
MT-ATP8ENST00000361851.1 linkuse as main transcript upstream_gene_variant P1

Frequencies

GnomAD4 exome
Cov.:
0
We have no GnomAD4 genomes data on this position. Probably position not covered by the project.
Gnomad homoplasmic
AF:
0.0
AC:
0
AN:
56419
Gnomad heteroplasmic
AF:
0.00011
AC:
6
AN:
56419

Mitomap

MERRF|-Other---LD-/-depressive-mood-disorder-/-leukoencephalopathy-/-HiCM-/-lipomas

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:15Other:2
Revision: reviewed by expert panel
LINK: link

Submissions by phenotype

MERRF syndrome Pathogenic:4Other:1
Pathogenic, criteria provided, single submitterclinical testingUndiagnosed Diseases Network, NIHJul 09, 2020This is a known pathogenic variant that accounts for about 80% of individuals with MERRF. -
Pathogenic, no assertion criteria providedliterature onlyOMIMOct 01, 2010- -
Pathogenic, criteria provided, single submitterclinical testingMGZ Medical Genetics CenterMay 31, 2022- -
Likely pathogenic, criteria provided, single submitterclinical testingInstitute of Human Genetics, University of Leipzig Medical CenterApr 07, 2022_x000D_ Criteria applied: PS4, PS3_SUP, PP1, PP3 -
not provided, no classification providedliterature onlyGeneReviews-Most common pathogenic variant; identified in more than 80% of persons w/MERRF -
not provided Pathogenic:3
Pathogenic, criteria provided, single submitterclinical testingCenter for Pediatric Genomic Medicine, Children's Mercy Hospital and ClinicsAug 26, 2014- -
Pathogenic, criteria provided, single submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesMay 12, 2017- -
Pathogenic, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenDec 01, 2019- -
Mitochondrial disease Pathogenic:2
Pathogenic, reviewed by expert panelcurationClinGen Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel, ClinGenNov 03, 2021The 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. -
Pathogenic, no assertion criteria providedclinical testingWellcome Centre for Mitochondrial Research, Newcastle UniversityMay 22, 2017- -
Juvenile myopathy, encephalopathy, lactic acidosis AND stroke Pathogenic:2
Pathogenic, criteria provided, single submitterclinical testingWong Mito Lab, Molecular and Human Genetics, Baylor College of MedicineJul 12, 2019The 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 -
Pathogenic, criteria provided, single submitterclinical testingMendelicsMay 04, 2022- -
Leigh syndrome Pathogenic:1Other:1
Pathogenic, no assertion criteria providedliterature onlyOMIMOct 01, 2010- -
not provided, no classification providedliterature onlyGeneReviews-- -
MT-TK-related disorder Pathogenic:1
Pathogenic, no assertion criteria providedclinical testingUndiagnosed Diseases Network, NIHMar 09, 2023- -
MT-TK-related mitochondrial disorder Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingBreda Genetics srlJul 20, 2021The 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
Pathogenic, no assertion criteria providedliterature onlyOMIMOct 01, 2010- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
Mitotip
Uncertain
11
Hmtvar
Pathogenic
0.90

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs118192098; hg19: chrM-8345; API