Submissions for variant NC_012920.1(MT-TK):m.8344A>G

dbSNP: rs118192098

Total submissions: 18

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel, ClinGen	RCV000495310	SCV002037594	pathogenic	Mitochondrial disease	2021-11-03	reviewed by expert panel	curation	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.
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000224965	SCV000281618	pathogenic	not provided	2014-08-26	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000224965	SCV000493135	pathogenic	not provided	2019-12-01	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000224965	SCV000884155	pathogenic	not provided	2017-05-12	criteria provided, single submitter	clinical testing
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine	RCV000850950	SCV000993184	pathogenic	MELAS syndrome	2019-07-12	criteria provided, single submitter	clinical testing	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
Undiagnosed Diseases Network, NIH	RCV000010192	SCV001432759	pathogenic	MERRF syndrome	2020-07-09	criteria provided, single submitter	clinical testing	This is a known pathogenic variant that accounts for about 80% of individuals with MERRF.
Breda Genetics srl	RCV001729345	SCV001977008	pathogenic	MT-TK-related mitochondrial disorder	2021-07-20	criteria provided, single submitter	clinical testing	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).
Institute of Human Genetics, University of Leipzig Medical Center	RCV000010192	SCV002505590	pathogenic	MERRF syndrome	2024-04-16	criteria provided, single submitter	clinical testing	Criteria applied: PS4_VSTR,PP1_MOD,PS3_SUP,PP3
Mendelics	RCV000850950	SCV002517700	pathogenic	MELAS syndrome	2022-05-04	criteria provided, single submitter	clinical testing
MGZ Medical Genetics Center	RCV000010192	SCV002579956	pathogenic	MERRF syndrome	2022-05-31	criteria provided, single submitter	clinical testing
OMIM	RCV000010192	SCV000030415	pathogenic	MERRF syndrome	2010-10-01	no assertion criteria provided	literature only
OMIM	RCV000010193	SCV000030416	pathogenic	Leigh syndrome	2010-10-01	no assertion criteria provided	literature only
OMIM	RCV000010194	SCV000030417	pathogenic	Parkinson disease, mitochondrial	2010-10-01	no assertion criteria provided	literature only
GeneReviews	RCV000010193	SCV000188890	not provided	Leigh syndrome		no assertion provided	literature only
GeneReviews	RCV000010192	SCV000207614	not provided	MERRF syndrome		no assertion provided	literature only	Most common pathogenic variant; identified in more than 80% of persons w/MERRF
Wellcome Centre for Mitochondrial Research, Newcastle University	RCV000495310	SCV000577896	pathogenic	Mitochondrial disease	2017-05-22	no assertion criteria provided	clinical testing
Undiagnosed Diseases Network, NIH	RCV003492290	SCV004242200	pathogenic	MT-TK-related disorder	2023-03-09	no assertion criteria provided	clinical testing
Solve-RD Consortium	RCV004766996	SCV005199977	likely pathogenic	Complex hereditary spastic paraplegia	2022-06-01	no assertion criteria provided	provider interpretation	Variant confirmed as disease-causing by referring clinical team