rs118192103

Variant names:

• chrM-8342-G-A
• rs118192103
• unassigned_transcript_4803:c.48G>A

Your query was ambiguous. Multiple possible variants found:

• chrM-8342-G-A
• chrM-8342-G-T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PP3 PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The m.8342G>A variant in MT-TK has been reported in one individual with primary mitochondrial disease to date (PMID:10220860), in a woman with ophthalmoplegia, ptosis, fatigue, muscle weakness, resting tremor, and myoclonic jerks. Muscle biopsy showed COX-negative fibers and decreased electron transport chain enzyme activities. The variant was present at 80% heteroplasmy in muscle and was undetectable in blood lymphocytes. The variant was also undetectable in blood lymphocytes from her asymptomatic mother, maternal aunt, and daughter. As the variant was also undetectable in this tissue in the proband, this cannot be considered a confirmed de novo occurrence. Single fiber testing in the proband showed higher levels of the variant in COX negative fibers (74%, n=26) than in COX positive fibers (53%, n=28), p<0.0003 (PS3_supporting, PMID:10220860). There are no cybrids or other functional analyses reported for this variant. There is one additional reported individual with the variant in the medical literature, however the heteroplasmy levels are too low (3-4%) to be causative of the clinical features noted (febrile infection-related epilepsy syndrome, or FIRES; PMID:37077567). This variant is absent in the MITOMAP GenBank dataset and gnomAD v3.1.2, and there is one heteroplasmic occurrence in the Helix dataset (PM2_supporting). The computational predictor MitoTIP suggests this variant is pathogenic (77.2 percentile) and HmtVAR predicts it to be pathogenic score of 0.65 (PP3). In summary, this variant meets criteria to be classified as uncertain significance 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 July 24, 2023. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID:32906214): PS3_supporting, PM2_supporting, PP3. LINK:https://erepo.genome.network/evrepo/ui/classification/CA120556/MONDO:0044970/015

• Frequency: Mitomap GenBank: 𝑓 0.0 (AC: 0)
• Consequence: TRNK unassigned_transcript_4803 synonymous
• Scores: Mitotip Pathogenic 16
• Clinical Significance: Uncertain significance reviewed by expert panel P:1 U:3 PEO-and-Myoclonus
• Conservation: PhyloP100: 0.0200
• Publications: 4 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: 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.48G>A		non_coding_transcript_exon	Exon 1 of 1
	MT-ATP6	ENST00000361899.2	TSL:6	c.-185G>A		upstream_gene	N/A	ENSP00000354632.2
	MT-ATP8	ENST00000361851.1	TSL:6	c.-24G>A		upstream_gene	N/A	ENSP00000355265.1

Frequencies

Mitomap GenBank AF: 0.0 AC: 0

Mitomap

Disease(s): PEO-and-Myoclonus

Status: Reported-[VUS]

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	2	-	not specified (2)
-	1	-	Mitochondrial disease (1)
1	-	-	Progressive external ophthalmoplegia with myoclonus (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
Mitotip	Pathogenic	16
Hmtvar	Pathogenic	0.65
PhyloP100		0.020

Other links and lift over

dbSNP: rs118192103; hg19: chrM-8343;