rs121434462

Variant names:

• chrM-12315-G-A
• rs121434462
• unassigned_transcript_4814:c.50G>A

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2 PP5_Very_Strong

Variant has been reported in ClinVar as Likely pathogenic (★★★).

• Frequency: Mitomap GenBank: Absent
• Consequence: TRNL2 stop_gained
• Scores: Mitotip Pathogenic 17
• Clinical Significance: Likely pathogenic reviewed by expert panel P:3 CPEO-/-KSS-/-possible-carotid-atherosclerosis-risk+-trend-toward-myocardial-infarction-risk
• Conservation: PhyloP100: 7.34

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 Pathogenic. Variant got 10 ACMG points.

• PM2: No frequency data in Mitomap. Probably very rare.
• PP5: Variant M-12315-G-A is Pathogenic according to our data. Variant chrM-12315-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 9586.Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRNL2	unassigned_transcript_4814	c.50G>A	p.Trp17*	stop_gained	Exon 1 of 1
ND5	unassigned_transcript_4815	c.-22G>A		upstream_gene_variant
ND4	unassigned_transcript_4811	c.*178G>A		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

CPEO-/-KSS-/-possible-carotid-atherosclerosis-risk+-trend-toward-myocardial-infarction-risk

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3

Revision: reviewed by expert panel

Submissions by phenotype

Mitochondrial disease Pathogenic:1

Nov 30, 2022

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

Significance: Likely pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The m.12315G>A variant in MT-TL2 has been reported in five affected and unrelated individuals from five families (PMIDs: one subject is reported in three different publications – 8923013, 9361028, 10332036; other subjects are reported in 12398839, 19718780, 18977334, 21819490; PS4_moderate). Age of onset ranged from childhood to adulthood (30s) and features included chronic progressive external ophthalmoplegia (CPEO), myopathy, pigmentary retinopathy, and sensorineural hearing loss. Muscle biopsies showed ragged red fibers, COX-deficiency, and reduced respiratory chain enzyme activities. Heteroplasmy levels ranged from 62-94% in muscle, from undetectable to 17% in blood, and were absent when assessed in other tissues. This variant occurred de novo in one individual (variant absent in blood, urine, and hair from healthy mother; PM6_supporting, PMID: 12398839). There were no similarly affected family members and no reports of transmission within a family to consider for evidence of segregation. This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). Single fiber testing was performed in two separate instances. This was first reported in 1996 (PMID: 8923013) and showed higher levels of the variant in fibers with no detectable COX activity (95 ± 1%, range 93–98%) than in apparently normal fibers (54 ± 33%, range 11 to 90%). Single fiber studies were again performed on a different subject in 2002 (PMID: 12398839) and revealed higher levels of the variant in COX-negative fibers (N=7, 75.34 ± 5.19% heteroplasmy, range 67.01–81.86%) than in COX-positive fibers (N=6, 32.20 ± 9.05% heteroplasmy, range 16.29–34.93%; PS3_supporting). The computational predictor MitoTIP suggests this variant is pathogenic (82.2 percentile) and HmtVAR predicts it to be pathogenic score of 0.85 (PP3). In summary, this variant meets criteria to be classified as likely pathogenic 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 November 30, 2022. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS4_moderate, PM6_supporting, PM2_supporting, PS3_supporting, PP3. -

MELAS syndrome Pathogenic:1

Jul 12, 2019

Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The NC_012920.1:m.12315G>A variant in MT-TL2 gene is interpreted to be a Pathogenic variant based on the modified ACMG guidelines (unpublished). This variant meets the following evidence codes reported in the guidelines: PS3, PS5, PM7 -

Mitochondrial encephalomyopathy Pathogenic:1

Nov 01, 1996

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
Mitotip	Pathogenic	17
Hmtvar	Pathogenic	0.85

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs121434462; hg19: chrM-12316;