rs121434462

Variant names:

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

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PS4_Moderate PM6_Supporting PS3_Supporting PP3 PM2_Supporting

This summary comes from the ClinGen Evidence Repository: 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. LINK:https://erepo.genome.network/evrepo/ui/classification/CA120558/MONDO:0044970/014

• Frequency: Mitomap GenBank: Absent
• Consequence: TRNL2 unassigned_transcript_4814 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
• 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: Likely_pathogenic. The variant received 6 ACMG points.

• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM6: 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: 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.50G>A		non_coding_transcript_exon	Exon 1 of 1
	MT-ND5	ENST00000361567.2	TSL:6	c.-22G>A		upstream_gene	N/A	ENSP00000354813.2
	MT-ND4	ENST00000361381.2	TSL:6	c.*178G>A		downstream_gene	N/A	ENSP00000354961.2

Frequencies

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

Alfa AF: 0.0000544 Hom.: 1

Mitomap

Disease(s): CPEO-/-KSS-/-possible-carotid-atherosclerosis-risk+-trend-toward-myocardial-infarction-risk

Status: Cfrm-[LP]

ClinVar

ClinVar submissions as Germline

Significance: Likely pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
1	-	-	MELAS syndrome (1)
1	-	-	Mitochondrial disease (1)
1	-	-	Mitochondrial encephalomyopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
Mitotip	Pathogenic	17
Hmtvar	Pathogenic	0.85
PhyloP100		7.3

Other links and lift over

dbSNP: rs121434462; hg19: chrM-12316;