M-12320-A-G

Variant names:

• chrM-12320-A-G
• rs121434463
• unassigned_transcript_4814:c.55A>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PS3_Supporting PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The m.12320A>G variant in MT-TL2 has been reported in one individual with primary mitochondrial disease to date (PMID:9012410), in a woman with progressive myopathy, acidosis, ptosis, and ragged red and COX-negative fibers on muscle biopsy. The variant was present at 70% heteroplasmy in muscle on first biopsy and was found to be present at 90% on subsequent biopsy, coinciding with a 12-year progression in symptoms. There is no report of her family members being testing and there are no additional reports of large families with this variant segregating with disease. This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). Computational predictors are conflicting (MitoTIP: 37.3%; HmtVAR: 0.7). Single fiber testing showed higher levels of the variant in COX-negative fibers (88-96%) compared to COX positive fibers (60-88%; PMID:9450773; PS3_supporting). 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 April 22, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID:32906214): PM2_supporting, PS3_supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA254838/MONDO:0044970/014

• Frequency: Mitomap GenBank: Absent
• Consequence: TRNL2 unassigned_transcript_4814 missense
• Scores: Mitotip Uncertain 11
• Clinical Significance: Uncertain significance reviewed by expert panel P:1 U:1 MM
• Conservation: PhyloP100: 6.82
• Publications: 1 publications found

Genes affected

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

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]

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

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

TRNS2 Gene-Disease associations (from GenCC):

• mitochondrial disease

  Inheritance: Mitochondrial Classification: MODERATE Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000387456.1. 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-TL2	ENST00000387456.1	TSL:6	n.55A>G		non_coding_transcript_exon	Exon 1 of 1
	MT-ND5	ENST00000361567.2	TSL:6	c.-17A>G		upstream_gene	N/A	ENSP00000354813.2
	MT-ND4	ENST00000361381.2	TSL:6	c.*183A>G		downstream_gene	N/A	ENSP00000354961.2

Frequencies

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

Alfa AF: 0.00 Hom.: 0

Mitomap

Disease(s): MM

Status: Reported

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
1	-	-	Inborn mitochondrial myopathy (1)
-	1	-	Mitochondrial disease (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
Mitotip	Uncertain	11
Hmtvar	Pathogenic	0.70
PhyloP100		6.8

Other links and lift over

dbSNP: rs121434463; hg19: chrM-12321;