rs121434463

Variant names:

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

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

Variant has been reported in ClinVar as Uncertain significance (★★★).

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

Genes affected

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

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]

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))

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: No frequency data in Mitomap. Probably very rare.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRNL2	unassigned_transcript_4814	c.55A>G	p.Asn19Asp	missense_variant	Exon 1 of 1
ND5	unassigned_transcript_4815	c.-17A>G		upstream_gene_variant
ND4	unassigned_transcript_4811	c.*183A>G		downstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt

Frequencies

GnomAD4 exome Cov.: 0

We have no GnomAD4 genomes data on this position. Probably position not covered by the project.

Mitomap

MM

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

Inborn mitochondrial myopathy Pathogenic:1

Feb 01, 1997

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Mitochondrial disease Uncertain:1

Apr 22, 2024

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.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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
Mitotip	Uncertain	11
Hmtvar	Pathogenic	0.70

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs121434463; hg19: chrM-12321;