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 1 ACMG points: 2P and 1B. PM2 BP7

The ENST00000000000(TRNK):​c.48G>A​(p.Glu16Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Mitomap GenBank: 𝑓 0.0 (AC: 0)
• Consequence: TRNK ENST00000000000 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 1 ACMG points.

• PM2: Very low frequency in mitomap database: 0.0
• BP7: Synonymous conserved (PhyloP=0.02 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRNK	unassigned_transcript_4803	c.48G>A	p.Glu16Glu	synonymous_variant	Exon 1 of 1
ATP6	unassigned_transcript_4805	c.-185G>A		upstream_gene_variant
ATP8	unassigned_transcript_4804	c.-24G>A		upstream_gene_variant
COX2	unassigned_transcript_4802	c.*73G>A		downstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MT-TK	ENST00000387421.1	n.48G>A		non_coding_transcript_exon_variant	Exon 1 of 1	6
MT-ATP6	ENST00000361899.2	c.-185G>A		upstream_gene_variant		6		ENSP00000354632.2
MT-ATP8	ENST00000361851.1	c.-24G>A		upstream_gene_variant		6		ENSP00000355265.1
MT-CO2	ENST00000361739.1	c.*73G>A		downstream_gene_variant		6		ENSP00000354876.1

Frequencies

Mitomap GenBank AF: 0.0 AC: 0

Mitomap

Disease(s): PEO-and-Myoclonus

Status: Reported-[VUS]

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:3

Revision: reviewed by expert panel

Submissions by phenotype

not specified Uncertain:2

May 04, 2022

Mendelics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 02, 2011

Stanford Center for Inherited Cardiovascular Disease, Stanford University

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. MT-TK m.8342G>A We classify it as a variant of uncertain significance. This variant has not been reported in association with cardiomyopathy in previous publications. It has been reported in association with an unspecified neuromuscular disorder. Tiranti et al (1999) describe an individual with muscle weakness, ophthalmoparesi s and this variant present with 80% heteroplasmy in muscle mtDNA and no heteroplasmy in lymphocyte DNA. The location of the nucleotide change is expected to alter the secondary structure of the resulting tRNA. A number of additional variants in this region of the MT-TK gene have been reported in association with mitochondrial disorders. This variant has not been reported in 6391 individuals at GeneDx, 2704 individuals in mtDB (www.genpath.uu.se/mtDB), 3735 individuals in MitoWheel (http://mitowheel.org/mitowheel.html). Triantis et al (1999) reported that m.8342G>A was not present in 100 presumably healthy controls. Thus in total this variant has not been detected in over 10,000 individuals. -

Progressive external ophthalmoplegia with myoclonus Pathogenic:1

Mar 01, 1999

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Mitochondrial disease Uncertain:1

Jul 24, 2023

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

Significance: Uncertain significance

Review Status: reviewed by expert panel

Collection Method: curation

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. -

Computational scores

Source: dbNSFP v4.3

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;