M-3255-G-A

Position:

• chrM-3255-G-A

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2 PP3 PP5_Very_Strong

The ENST00000386347.1(MT-TL1):​n.26G>A variant causes a non coding transcript exon change. Variant has been reported in ClinVar as Likely pathogenic (★★★).

• Frequency: Mitomap GenBank: 𝑓 0.0 (AC: 0)
• Consequence: MT-TL1 ENST00000386347.1 non_coding_transcript_exon
• Scores: Mitotip Pathogenic 16
• Clinical Significance: Likely pathogenic reviewed by expert panel P:3 MERRF-/-KSS-overlap
• Conservation: PhyloP100: 5.38

Genes affected

MT-TL1 (HGNC:7490): (mitochondrially encoded tRNA leucine 1 (UUA/G)) Implicated in cardiomyopathy. [provided by Alliance of Genome Resources, Apr 2022]

TRNL1 (HGNC:):

MT-RNR2 (HGNC:7471): (mitochondrially encoded 16S RNA) Enables G protein-coupled receptor binding activity; protein self-association; and receptor antagonist activity. Involved in several processes, including leukocyte chemotaxis; negative regulation of cell death; and negative regulation of neuroinflammatory response. Located in several cellular components, including mitochondrion; perinuclear region of cytoplasm; and sperm midpiece. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PM2: Very low frequency in mitomap database: 0.0
• PP3: Mitotip and hmtvar scores support pathogenic criterium.
• PP5: Variant M-3255-G-A is Pathogenic according to our data. Variant chrM-3255-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 689861.Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TRNL1	TRNL1.1	n.26G>A		non_coding_transcript_exon_variant	1/1
RNR2	RNR2.1			downstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MT-TL1	ENST00000386347.1	n.26G>A		non_coding_transcript_exon_variant	1/1
MT-RNR2	ENST00000387347.2			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 GenBank AF: 0.0 AC: 0

Mitomap

MERRF-/-KSS-overlap

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3

Revision: reviewed by expert panel

Submissions by phenotype

MELAS syndrome Pathogenic:2

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.3255G>A variant in MT-TL1 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, PM7, PM8, PM9 -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 04, 2022	- -

Mitochondrial disease Pathogenic:1

Likely pathogenic, reviewed by expert panel

curation

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

Apr 22, 2024

The m.3255G>A variant in MT-TL1 has been reported in two unrelated families with primary mitochondrial disease to date (PMIDs: 2413483, 12868503). The age of onset was the fifth decade and clinical features included myopathy, lactic acidosis, seizures, pigmentary retinopathy, ptosis, neuropathy, elevated cerebrospinal fluid protein, and ragged red and COX-deficient fibers (PS4_supporting). This variant segregated with clinical manifestations in one of these families as the variant was present in the proband at 53% heteroplasmy in skeletal muscle, 67% in urine sediment, less than 2% in cultured skin fibroblasts, and 22% in blood. The variant was present at less than 2% heteroplasmy in leukocytes from the mother and sister. An additional seven unaffected family members had the variant present at less than 2% in urine and saliva, and the variant was undetectable in another family member (PP1_moderate; PMID: 12868503). There are no individuals reported with de novo occurrences of this variant to our knowledge. This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). The computational predictor MitoTIP suggests this variant is deleterious (75.8 percentile) and HmtVAR predicts it to be deleterious with a score of 0.7 (PP3). Single fiber testing showed higher levels of the variant in COX-negative fibers (94%) than in COX-positive fibers (18%; p<0.0001; PS3_supporting; PMID: 12868503). 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 April 22, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS4_supporting, PP1_moderate, PM2_supporting, PS3_supporting. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
Mitotip	Pathogenic	16
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: rs1603218856; hg19: chrM-3256;