rs118192100

chrM-8363-G-A

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2 PP3 PP5_Very_Strong

The ENST00000387421.1(MT-TK):n.69G>A variant causes a non coding transcript exon change. Variant has been reported in ClinVar as Likely pathogenic (★★★).

• Frequency: Mitomap GenBank: Absent
• Consequence: MT-TK ENST00000387421.1 non_coding_transcript_exon
• Scores: Mitotip Pathogenic 19
• Clinical Significance: Likely pathogenic reviewed by expert panel P:4 O:2 MICM+DEAF-/-MERRF-/-Autism-/-Leigh-Syndrome-/-Ataxia
• Conservation: PhyloP100: 5.17

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 11 ACMG points.

• PM2: No frequency data in Mitomap. Probably very rare.
• PP3: Mitotip and hmtvar scores support pathogenic criterium.
• PP5: Variant M-8363-G-A is Pathogenic according to our data. Variant chrM-8363-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 9581.Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TRNK	TRNK.1	n.69G>A		non_coding_transcript_exon_variant	1/1
ATP8	ATP8.1			upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MT-TK	ENST00000387421.1	n.69G>A		non_coding_transcript_exon_variant	1/1
MT-ATP8	ENST00000361851.1			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: 56434

Gnomad heteroplasmic AF: 0.000018 AC: 1 AN: 56434

Mitomap

MICM+DEAF-/-MERRF-/-Autism-/-Leigh-Syndrome-/-Ataxia

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:4 Other:2

Revision: reviewed by expert panel

Submissions by phenotype

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

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.8363G>A 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 -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 04, 2022	- -

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.8363G>A variant in MT-TK has been reported in at least 30 individuals with primary mitochondrial disease from 12 kindreds. Features seen in affected individuals include Leigh syndrome and myoclonic epilepsy with ragged red fibers (MERRF), as well as myopathy, peripheral neuropathy, ataxia, cardiomyopathy, sensorineural hearing loss, ophthalmoplegia, and lipomas. Heteroplasmy levels of this variant in affected individuals is variable, ranging from 40-97% (PS4_moderate; PMIDs: 8651277, 9052804, 10868777, 11108511, 19278689, 18319067, 19370763, 10102446, 16326995, 9932960). This variant segregated with disease in multiple affected family members in multiple families and several healthy family members had lower to undetectable levels (PP1_moderate; PMIDs: 9052804, 10868777, 10102446, 9932960). There are no confirmed de novo occurrences of this variant to our knowledge. The computational predictor MitoTIP suggests this variant impacts the function of this tRNA with a score of 94.3 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). Single fiber testing and cybrid analysis further support the functional impact of this variant (PS3_suporting). Single fiber testing showed the variant was significantly higher in COX-negative ragged red fibers (n = 5; 97.3% ± 2.5) than in normal fibers (n = 5; 89.2 ± 8.3; p < 0.05; PMID: 9932960). Cybrid studies showed that clones with the variant present at homoplasmy had statistically significant decreases in Complex I, ATP synthase, and oxygen consumption (PMIDs: 15554876, 25909222). In summary, this variant meets criteria to be classified as likely pathogenic for primary mitochondrial disease inherited in a mitochondrial 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): PS4_moderate, PP3, PP1_moderate, PS3_supporting, PM2_supporting. -

Cardiomyopathy and Deafness Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

May 01, 1996

- -

MERRF syndrome Other:1

not provided, no classification provided

literature only

GeneReviews

-

Pathogenic variants identified in approximately 10% of persons w/MERRF -

Leigh syndrome Other:1

not provided, no classification provided

literature only

GeneReviews

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
Mitotip	Pathogenic	19
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: rs118192100; hg19: chrM-8364;