M-12316-G-A

Position:

• chrM-12316-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PS4_Supporting PM2_Supporting PS3_Supporting PP3

This summary comes from the ClinGen Evidence Repository: The m.12316G>A variant in MT-TL2 has been reported in three unrelated individuals with primary mitochondrial disease. The three individuals had chronic progressive external ophthalmoplegia (CPEO). Other features seen included peripheral neuropathy, myopathy, and exercise intolerance. Muscle biopsy in affected individuals revealed ragged red fibers, COX-negative fibers, and decreased activities of respiratory chain complexes I and IV. The levels of the variant in affected individuals ranged from 40-55.6% in muscle when reported. Levels in other tissues varied from undetectable to 10% (PS4_supporting; PMIDs: 23847141, 20163808, 18603265). There are no large families reported in the medical literature to consider for evidence of segregation. There are no reported de novo occurrences of this variant to our knowledge. The computational predictor MitoTIP suggests this variant impacts the function of this tRNA (83.7 percentile) as does HmtVar with a score of 0.6 (PP3). This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). Single fiber testing showed a higher degree of heteroplasmy in ragged red fibers (87.4% ± 8.5, n = 4) and COX-deficient fibers (59.7% ± 27.8, n = 4) compared to COX-positive muscle fibers (wild type mtDNA only, n = 6, Fig. 2). The difference between COX-positive and ragged red fibers was statistically significant (p<0.00001; PMID:20163808; 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 February 27, 2023. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID:32906214): PS4_supporting, PM2_supporting, PP3, PS3_supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA913170089/MONDO:0044970/015

• Frequency: Mitomap GenBank: Absent
• Consequence: MT-TL2 ENST00000387456.1 non_coding_transcript_exon
• Scores: Mitotip Pathogenic 18
• Clinical Significance: Uncertain significance reviewed by expert panel U:1 CPEO-/-mitochondrial-myopathy
• Conservation: PhyloP100: 9.25

Genes affected

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

TRNL2 (HGNC:):

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 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.
• PP3: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TRNL2	TRNL2.1	n.51G>A		non_coding_transcript_exon_variant	1/1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MT-TL2	ENST00000387456.1	n.51G>A		non_coding_transcript_exon_variant	1/1
MT-ND5	ENST00000361567.2			upstream_gene_variant				ENSP00000354813	P1

Frequencies

GnomAD4 exome Cov.: 0

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

Mitomap

CPEO-/-mitochondrial-myopathy

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

Mitochondrial disease Uncertain:1

Uncertain significance, reviewed by expert panel

curation

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

Feb 27, 2023

The m.12316G>A variant in MT-TL2 has been reported in three unrelated individuals with primary mitochondrial disease. The three individuals had chronic progressive external ophthalmoplegia (CPEO). Other features seen included peripheral neuropathy, myopathy, and exercise intolerance. Muscle biopsy in affected individuals revealed ragged red fibers, COX-negative fibers, and decreased activities of respiratory chain complexes I and IV. The levels of the variant in affected individuals ranged from 40-55.6% in muscle when reported. Levels in other tissues varied from undetectable to 10% (PS4_supporting; PMIDs: 23847141, 20163808, 18603265). There are no large families reported in the medical literature to consider for evidence of segregation. There are no reported de novo occurrences of this variant to our knowledge. The computational predictor MitoTIP suggests this variant impacts the function of this tRNA (83.7 percentile) as does HmtVar with a score of 0.6 (PP3). This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). Single fiber testing showed a higher degree of heteroplasmy in ragged red fibers (87.4% ± 8.5, n = 4) and COX-deficient fibers (59.7% ± 27.8, n = 4) compared to COX-positive muscle fibers (wild type mtDNA only, n = 6, Fig. 2). The difference between COX-positive and ragged red fibers was statistically significant (p<0.00001; PMID: 20163808; 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 February 27, 2023. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS4_supporting, PM2_supporting, PP3, PS3_supporting. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
Mitotip	Pathogenic	18
Hmtvar	Pathogenic	0.60

Splicing

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chrM-12317;