rs118192099

Variant names:

• chrM-8356-T-C
• rs118192099
• unassigned_transcript_4803:c.62T>C

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PP1_Moderate PS3_Supporting PP3 PS4_Supporting PM2_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: TRNK unassigned_transcript_4803 missense
• Scores: Mitotip Pathogenic 18
• Clinical Significance: Likely pathogenic reviewed by expert panel P:5 O:1 MERRF
• Conservation: PhyloP100: 4.74
• Publications: 2 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: Likely_pathogenic. The variant received 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.

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.62T>C		non_coding_transcript_exon	Exon 1 of 1
	MT-ATP6	ENST00000361899.2	TSL:6	c.-171T>C		upstream_gene	N/A	ENSP00000354632.2
	MT-ATP8	ENST00000361851.1	TSL:6	c.-10T>C		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: 56434

Gnomad heteroplasmic AF: 0.000035 AC: 2 AN: 56434

Mitomap

Disease(s): MERRF

Status: Cfrm-[LP]

ClinVar

ClinVar submissions as Germline

Significance: Likely pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
2	-	-	MELAS syndrome (2)
1	-	-	MERRF syndrome (2)
1	-	-	MERRF/MELAS overlap syndrome (1)
1	-	-	Mitochondrial disease (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
Mitotip	Pathogenic	18
Hmtvar	Pathogenic	0.75
PhyloP100		4.7

Other links and lift over

dbSNP: rs118192099; hg19: chrM-8357;