rs118192099

Positions:

• chrM-8356-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PP3 PS4_Supporting PM2_Supporting PP1_Moderate PS3_Supporting

This summary comes from the ClinGen Evidence Repository: The m.8356T>C variant in MT-TK has been reported in at least 11 individuals from two kindreds with primary mitochondrial disease. Age of onset ranged from the first decade of life to adulthood. Features seen in affected individuals include myoclonic epilepsy with ragged red fibers (MERRF), ataxia, generalized seizures, hearing loss, and lactic acidosis. Heteroplasmy levels were consistently lower in blood and higher in muscle, ranging from 43.4% to homoplasmy (PMIDs: 8069654, 1361099; PS4_supporting). Of note, there is an additional family reported in the literature that was not considered for this variant curation given the presence of another pathogenic variant, m.3243A>G. These individuals had features similar to those seen in individuals with m.8356T>C, as well as features classic for mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS; PMID:20610441). This variant segregated with disease manifestations in multiple members of one family reported (PMID:8069654; PP1_moderate). There are no reported cases of de novo occurrences to our knowledge. The computational predictor MitoTIP suggests this variant impacts the function of this tRNA (88.8 percentile) as does HmtVar with a score of 0.75 (PP3). This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). In cybrid cell lines homoplasmic for this variant, reduced oxygen consumption was reported, supporting the functional impact of this variant (PMID:7739567; PS3_supporting). In summary, this variant meets criteria to be classified as likely pathogenic for primary mitochondrial disease inherited in a maternal manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on March 13, 2023. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID:32906214): PS3_supporting, PS4_supporting, PP1_moderate, PP3, PM2_supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA120554/MONDO:0044970/014

• Frequency: Mitomap GenBank: Absent
• Consequence: MT-TK ENST00000387421.1 non_coding_transcript_exon
• Scores: Mitotip Pathogenic 18
• Clinical Significance: Likely pathogenic reviewed by expert panel P:5 O:1 MERRF
• Conservation: PhyloP100: 4.74

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 Likely_pathogenic. Variant got 6 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.
• PM2: 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.62T>C		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.62T>C		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: 56434

Gnomad heteroplasmic AF: 0.000035 AC: 2 AN: 56434

Mitomap

MERRF

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:5 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

MELAS syndrome 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.8356T>C 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, PM7 -

MERRF syndrome Pathogenic:1 Other:1

not provided, no classification provided	literature only	GeneReviews	-	Pathogenic variants identified in approximately 10% of persons w/MERRF -
Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 01, 2010	- -

Mitochondrial disease Pathogenic:1

Likely pathogenic, reviewed by expert panel

curation

ClinGen Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel, ClinGen

Mar 13, 2023

The m.8356T>C variant in MT-TK has been reported in at least 11 individuals from two kindreds with primary mitochondrial disease. Age of onset ranged from the first decade of life to adulthood. Features seen in affected individuals include myoclonic epilepsy with ragged red fibers (MERRF), ataxia, generalized seizures, hearing loss, and lactic acidosis. Heteroplasmy levels were consistently lower in blood and higher in muscle, ranging from 43.4% to homoplasmy (PMIDs: 8069654, 1361099; PS4_supporting). Of note, there is an additional family reported in the literature that was not considered for this variant curation given the presence of another pathogenic variant, m.3243A>G. These individuals had features similar to those seen in individuals with m.8356T>C, as well as features classic for mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS; PMID: 20610441). This variant segregated with disease manifestations in multiple members of one family reported (PMID: 8069654; PP1_moderate). There are no reported cases of de novo occurrences to our knowledge. The computational predictor MitoTIP suggests this variant impacts the function of this tRNA (88.8 percentile) as does HmtVar with a score of 0.75 (PP3). This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). In cybrid cell lines homoplasmic for this variant, reduced oxygen consumption was reported, supporting the functional impact of this variant (PMID: 7739567; PS3_supporting). In summary, this variant meets criteria to be classified as likely pathogenic for primary mitochondrial disease inherited in a maternal manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on March 13, 2023. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS3_supporting, PS4_supporting, PP1_moderate, PP3, PM2_supporting. -

MERRF/MELAS overlap syndrome 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	Pathogenic	18
Hmtvar	Pathogenic	0.75

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs118192099; hg19: chrM-8357;