M-8344-A-G

Position:

• chrM-8344-A-G

Variant summary

Our verdict is Pathogenic. Variant got 8 ACMG points: 8P and 0B. PS4 PS3_Supporting PP1_Moderate PP3

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:16 O:2 MERRF|-Other---LD-/-depressive-mood-disorder-/-leukoencephalopathy-/-HiCM-/-lipomas
• Conservation: PhyloP100: -2.79

Genes affected

MT-TK (HGNC:7489): (mitochondrially encoded tRNA lysine)

TRNK (HGNC:):

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]

ACMG classification

Verdict is Pathogenic. Variant got 8 ACMG points.

• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PP1: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TRNK	TRNK.1	n.50A>G		non_coding_transcript_exon_variant	1/1
ATP8	ATP8.1			upstream_gene_variant			YP_003024030.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MT-TK	ENST00000387421.1	n.50A>G		non_coding_transcript_exon_variant	1/1
MT-ATP8	ENST00000361851.1			upstream_gene_variant				ENSP00000355265	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:16 Other:2

Revision: reviewed by expert panel

Submissions by phenotype

MERRF syndrome Pathogenic:4 Other:1

not provided, no classification provided	literature only	GeneReviews	-	Most common pathogenic variant; identified in more than 80% of persons w/MERRF -
Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 01, 2010	- -
Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	May 31, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Undiagnosed Diseases Network, NIH	Jul 09, 2020	This is a known pathogenic variant that accounts for about 80% of individuals with MERRF. -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Apr 16, 2024	Criteria applied: PS4_VSTR,PP1_MOD,PS3_SUP,PP3 -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Aug 26, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	May 12, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2019	- -

Mitochondrial disease Pathogenic:2

Pathogenic, reviewed by expert panel	curation	ClinGen Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel, ClinGen	Nov 03, 2021	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. -
Pathogenic, no assertion criteria provided	clinical testing	Wellcome Centre for Mitochondrial Research, Newcastle University	May 22, 2017	- -

Juvenile myopathy, encephalopathy, lactic acidosis AND stroke Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 04, 2022	- -
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.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:1 Other:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 01, 2010	- -
not provided, no classification provided	literature only	GeneReviews	-	- -

Complex hereditary spastic paraplegia Pathogenic:1

Likely pathogenic, no assertion criteria provided

provider interpretation

Solve-RD Consortium

Jun 01, 2022

Variant confirmed as disease-causing by referring clinical team -

MT-TK-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Undiagnosed Diseases Network, NIH

Mar 09, 2023

- -

MT-TK-related mitochondrial disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Breda Genetics srl

Jul 20, 2021

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

Pathogenic, no assertion criteria provided

literature only

OMIM

Oct 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

Other links and lift over

dbSNP: rs118192098; hg19: chrM-8345;