chrM-12207-G-A

Variant names:

• chrM-12207-G-A
• rs118203889
• unassigned_transcript_4813:c.1G>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PP3 PS4_Supporting PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The m.12207G>A variant in MT-TS2 has been reported in three individuals with primary mitochondrial disease to date. One person had clinical features consistent with myoclonic epilepsy with ragged red fibers (MERRF) and mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS; PMID:16950817), had complex I deficiency in muscle, and had the variant present at 92% heteroplasmy in muscle. The variant was undetectable in the mother’s blood. Another individual was reported as part of a primary mitochondrial disease cohort (PMID:27450679) and was found to have the variant present at >60% in muscle and was undetectable in blood from the proband and mother. The variant was also seen in a Japanese family with diabetes, epilepsy, deafness, and developmental delay. The variant was found in the proband at 31.3% heteroplasmy in blood, 52.6% in saliva, and 73.9% in urinary sediment while the variant was found in the mother at 13.8%, 22.1%, and 29.4%, respectively (PMID:36967720; PS4_supporting). This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). The computational predictor MitoTIP suggests this variant is deleterious (76.4 percentile) and HmtVAR predicts it to be deleterious with a score of 0.5 (PP3). There are no cybrids, single fiber studies, or other functional assays reported on this variant. 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 May 13, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID:32906214): PS4_supporting, PP3, PM2_supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA120545/MONDO:0044970/015

• Frequency: Mitomap GenBank: Absent
• Consequence: TRNS2 unassigned_transcript_4813 missense
• Scores: Mitotip Pathogenic 16
• Clinical Significance: Uncertain significance reviewed by expert panel P:2 U:1 O:1 Myopathy-/-Encephalopathy
• Conservation: PhyloP100: 0.419
• Publications: 1 publications found

Genes affected

TRNS2 (HGNC:7498): (mitochondrially encoded tRNA serine 2 (AGU/C))

MT-ND5 (HGNC:7461): (mitochondrially encoded NADH dehydrogenase 5) Enables NADH dehydrogenase (ubiquinone) activity. Involved in mitochondrial electron transport, NADH to ubiquinone and mitochondrial respiratory chain complex I assembly. Part of mitochondrial respiratory chain complex I. Implicated in Leber hereditary optic neuropathy; Leigh disease; and MELAS syndrome. [provided by Alliance of Genome Resources, Apr 2022]

MT-ND4 (HGNC:7459): (mitochondrially encoded NADH dehydrogenase 4) Enables NADH dehydrogenase (ubiquinone) activity. Involved in mitochondrial electron transport, NADH to ubiquinone and mitochondrial respiratory chain complex I assembly. Part of mitochondrial respiratory chain complex I. Implicated in Leber hereditary optic neuropathy; Parkinson's disease; macular degeneration; and schizophrenia. Biomarker of Alzheimer's disease. [provided by Alliance of Genome Resources, Apr 2022]

TRNL2 (HGNC:7491): (mitochondrially encoded tRNA leucine 2 (CUN))

TRNH (HGNC:7487): (mitochondrially encoded tRNA histidine)

TRNH Gene-Disease associations (from GenCC):

• mitochondrial disease

  Inheritance: Mitochondrial Classification: DEFINITIVE Submitted by: ClinGen
• MERRF syndrome

  Inheritance: Mitochondrial Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• 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: ENST00000387449.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

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

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MT-TS2	ENST00000387449.1	TSL:6	n.1G>A		non_coding_transcript_exon	Exon 1 of 1
	MT-ND5	ENST00000361567.2	TSL:6	c.-130G>A		upstream_gene	N/A	ENSP00000354813.2	P03915
	MT-ND4	ENST00000361381.2	TSL:6	c.*70G>A		downstream_gene	N/A	ENSP00000354961.2	P03905

Frequencies

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

Alfa AF: 0.00 Hom.: 0

Mitomap

Disease(s): Myopathy-/-Encephalopathy

Status: Reported

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
1	-	-	MELAS 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	16
Hmtvar	Pathogenic	0.50
PhyloP100		0.42

Other links and lift over

dbSNP: rs118203889; hg19: chrM-12208;