chrM-12276-G-A

Position:

• chrM-12276-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PP3 PM6_Supporting PS4_Moderate PS3_Supporting PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The m.12276G>A variant in MT-TL2 has been reported in four unrelated individuals with primary mitochondrial disease. Chronic progressive external ophthalmoplegia and myopathy were seen in three cases (PMIDs: 15649400, 15591266, 23847141), and two of these cases had pigmentary retinopathy (PMIDs: 15649400, 23847141). The fourth case had a progressive encephalopathy (PMID:20022607). Muscle biopsies in affected individuals showed ragged red fibers, COX-negative fibers, and normal to reduced respiratory chain enzyme activities. Heteroplasmy levels were consistently highest in muscle, ranging from 18-81%, and were low (6-8%) to undetectable in other tissues (PS4_moderate, PMIDs: 15649400, 15591266, 23847141, 20022607). The variant was confirmed to have occurred de novo in one of the reported individuals (variant absent in blood and urine of healthy mother and sister, PMID:20022607; PM6_supporting). There are no large families reported in the medical literature with testing performed to consider for evidence of segregation. The computational predictor MitoTIP suggests this variant is pathogenic (74.7 percentile) and HmtVAR predicts it to be pathogenic score of 0.65 (PP3). This variant is absent in the Helix dataset and gnomAD v3.1.2, and the single occurrence in the GenBank dataset is from an affected individual (PM2_supporting). Single fiber testing was performed in two of the four reported cases (PS3_supporting). In one case, fibers with <75% of the variant exhibited normal COX/SDH ratios and fibers with 80% or higher had severe deficiency of COX activity (PMID:15591266). In another individual (PMID:20022607), COX-deficient fibers had ~80% heteroplasmy and COX-positive fibers had ~25% heteroplasmy, a statistically significant difference (p<0.001). 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, PP3, PS3_supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA913169952/MONDO:0044970/014

• Frequency: Mitomap GenBank: Absent
• Consequence: MT-TL2 ENST00000387456.1 non_coding_transcript_exon
• Scores: Mitotip Uncertain 16
• Clinical Significance: Likely pathogenic reviewed by expert panel P:2 CPEO
• Conservation: PhyloP100: 7.41

Genes affected

MT-TL2 (HGNC:7491): (mitochondrially encoded tRNA leucine 2 (CUN))

TRNL2 (HGNC:):

MT-TS2 (HGNC:7498): (mitochondrially encoded tRNA serine 2 (AGU/C))

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TRNL2	TRNL2.1	n.11G>A		non_coding_transcript_exon_variant	1/1
TRNS2	TRNS2.1			downstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MT-TL2	ENST00000387456.1	n.11G>A		non_coding_transcript_exon_variant	1/1
MT-TS2	ENST00000387449.1			downstream_gene_variant

Frequencies

GnomAD4 exome Cov.: 0

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

Mitomap

CPEO

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: reviewed by expert panel

Submissions by phenotype

Mitochondrial disease Pathogenic:1

Likely pathogenic, reviewed by expert panel

curation

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

Nov 30, 2022

The m.12276G>A variant in MT-TL2 has been reported in four unrelated individuals with primary mitochondrial disease. Chronic progressive external ophthalmoplegia and myopathy were seen in three cases (PMIDs: 15649400, 15591266, 23847141), and two of these cases had pigmentary retinopathy (PMIDs: 15649400, 23847141). The fourth case had a progressive encephalopathy (PMID: 20022607). Muscle biopsies in affected individuals showed ragged red fibers, COX-negative fibers, and normal to reduced respiratory chain enzyme activities. Heteroplasmy levels were consistently highest in muscle, ranging from 18-81%, and were low (6-8%) to undetectable in other tissues (PS4_moderate, PMIDs: 15649400, 15591266, 23847141, 20022607). The variant was confirmed to have occurred de novo in one of the reported individuals (variant absent in blood and urine of healthy mother and sister, PMID: 20022607; PM6_supporting). There are no large families reported in the medical literature with testing performed to consider for evidence of segregation. The computational predictor MitoTIP suggests this variant is pathogenic (74.7 percentile) and HmtVAR predicts it to be pathogenic score of 0.65 (PP3). This variant is absent in the Helix dataset and gnomAD v3.1.2, and the single occurrence in the GenBank dataset is from an affected individual (PM2_supporting). Single fiber testing was performed in two of the four reported cases (PS3_supporting). In one case, fibers with <75% of the variant exhibited normal COX/SDH ratios and fibers with 80% or higher had severe deficiency of COX activity (PMID: 15591266). In another individual (PMID: 20022607), COX-deficient fibers had ~80% heteroplasmy and COX-positive fibers had ~25% heteroplasmy, a statistically significant difference (p<0.001). 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, PP3, PS3_supporting. -

Juvenile myopathy, encephalopathy, lactic acidosis AND stroke Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Jul 12, 2019

The NC_012920.1:m.12276G>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 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
Mitotip	Uncertain	16
Hmtvar	Pathogenic	0.65

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1603223645; hg19: chrM-12277;