rs118192098

Variant names:

• chrM-8344-A-G
• rs118192098
• unassigned_transcript_4803:c.50A>G

Variant summary

Our verdict is Pathogenic. The variant received 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: TRNK unassigned_transcript_4803 missense
• Scores: Mitotip Uncertain 11
• Clinical Significance: Pathogenic reviewed by expert panel P:20 O:2 MERRF|-Other---LD-/-depressive-mood-disorder-/-leukoencephalopathy-/-HiCM-/-lipomas
• Conservation: PhyloP100: -2.79
• Publications: 3 publications found

Genes affected

TRNK (HGNC:7489): (mitochondrially encoded tRNA lysine)

MT-ATP6 (HGNC:7414): (mitochondrially encoded ATP synthase 6) 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 Leber hereditary optic neuropathy; NARP syndrome; Parkinson's disease; multiple sclerosis; and systemic lupus erythematosus. [provided by Alliance of Genome Resources, Apr 2022]

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]

MT-CO2 (HGNC:7421): (mitochondrially encoded cytochrome c oxidase II) Contributes to cytochrome-c oxidase activity. Predicted to be involved in mitochondrial electron transport, cytochrome c to oxygen and positive regulation of vasoconstriction. Located in mitochondrial inner membrane. Part of respiratory chain complex IV. Biomarker of Huntington's disease and stomach cancer. [provided by Alliance of Genome Resources, Apr 2022]

MT-CO2 Gene-Disease associations (from GenCC):

• mitochondrial disease

  Inheritance: Mitochondrial Classification: DEFINITIVE Submitted by: ClinGen
• cytochrome-c oxidase deficiency disease

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• MELAS syndrome

  Inheritance: Mitochondrial Classification: SUPPORTIVE Submitted by: Orphanet
• Leigh syndrome

  Inheritance: Mitochondrial Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000387421.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
There are no transcript annotations for this variant.

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MT-TK	ENST00000387421.1	TSL:6	n.50A>G		non_coding_transcript_exon	Exon 1 of 1
	MT-ATP6	ENST00000361899.2	TSL:6	c.-183A>G		upstream_gene	N/A	ENSP00000354632.2
	MT-ATP8	ENST00000361851.1	TSL:6	c.-22A>G		upstream_gene	N/A	ENSP00000355265.1

Frequencies

Mitomap GenBank The variant is not present, suggesting it is rare .

Gnomad homoplasmic AF: 0.0 AC: 0 AN: 56419

Gnomad heteroplasmic AF: 0.00011 AC: 6 AN: 56419

Mitomap

Disease(s): MERRF|-Other---LD-/-depressive-mood-disorder-/-leukoencephalopathy-/-HiCM-/-lipomas

Status: Cfrm-[P]

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
5	-	-	MERRF syndrome (6)
4	-	-	not provided (4)
3	-	-	Mitochondrial disease (3)
2	-	-	MELAS syndrome (2)
1	-	-	Complex hereditary spastic paraplegia (1)
1	-	-	Leigh syndrome (2)
1	-	-	MT-TK-related disorder (1)
1	-	-	MT-TK-related mitochondrial disorder (1)
1	-	-	Parkinson disease, mitochondrial (1)
1	-	-	Thrombocythemia 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
Mitotip	Uncertain	11
Hmtvar	Pathogenic	0.90
PhyloP100		-2.8

Other links and lift over

dbSNP: rs118192098; hg19: chrM-8345;