rs199474659

chrM-3256-C-T

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.27C>T variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Likely pathogenic (★★★).

• Frequency: Mitomap GenBank: Absent
• Consequence: MT-TL1 ENST00000386347.1 non_coding_transcript_exon
• Scores: Mitotip Pathogenic 19
• Clinical Significance: Likely pathogenic reviewed by expert panel P:4 O:1 MELAS|-possible-atherosclerosis-risk
• Conservation: PhyloP100: 1.96

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: No frequency data in Mitomap. Probably very rare.
• PP3: Mitotip and hmtvar scores support pathogenic criterium.
• PP5: Variant M-3256-C-T is Pathogenic according to our data. Variant chrM-3256-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 9591.Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TRNL1	TRNL1.1	n.27C>T		non_coding_transcript_exon_variant	1/1
RNR2	RNR2.1			downstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MT-TL1	ENST00000386347.1	n.27C>T		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

MELAS|-possible-atherosclerosis-risk

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:4 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

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

not provided, no classification provided	literature only	GeneReviews	-	- -
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.3256C>T 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, PS5, PM7 -

MERRF syndrome Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Mar 01, 1998

- -

Mitochondrial disease Pathogenic:1

Likely pathogenic, reviewed by expert panel

curation

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

Aug 08, 2022

The m.3256C>T variant in MT-TL1 has been reported in four individuals in the literature and an additional four cases were seen by experts on this panel. Affected individuals had primary mitochondrial disease with variable features including MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes) phenotype, neurologic involvement (neurodegeneration/dementia, stroke-like episodes, recurrent encephalopathy, seizures, ataxia, myoclonus); neuromuscular involvement (muscle atrophy, progressive myopathy); cardiac involvement (cardiac failure); ophthalmologic involvement (ophthalmoplegia, ptosis, central vision loss); ENT involvement (hearing loss); endocrine involvement (hashimoto thyroiditis, diabetes mellitus); lab abnormalities (elevated blood and CSF lactate and pyruvate); and brain imaging findings (progressive brain atrophy); with heteroplasmy levels in multiple tissues ranging from 8% - 98% (PS4_moderate; PMIDs: 19941338, 10953207, 7804130, 8254046). This variant segregated with disease in a single reported family as the proband’s healthy sister had undetectable levels of variant in blood; the proband’s mother was decreased; and the proband was heteroplasmic for the variant in numerous tissues: 64% (muscle), 8% (white blood cells), 48% (first passage cultured fibroblasts), and 18% (hair roots) (PP1; PMID: 8254046). There are no reports of de novo occurrences of this variant to our knowledge. Ragged red fiber (RRF) analysis in muscle noted only partially impaired COX activity. However, when analyzed for levels of mutant genomes, RRFs were essentially homoplasmic for mutant mtDNAs (range 94-97%). Normal (non-RRFs) had much lower levels of mutant genomes (34-75%). The percentage of mutant mtDNA in total the muscle was 64% (PS3_supporting: PMID: 8254046). This variant is absent from Mitomap's 51,863 sequences (AF=0.00%); Helix's 196,554 sequences (AF=0.00%); and gnomAD v3.1.2 (PM2_supporting). The computational predictor MitoTIP suggests this variant impacts the function of this tRNA with a score of 93.70%, as does HmtVar with a score of 0.75 (PP3). In summary, this variant meets criteria to be classified as likely pathogenic for primary mitochondrial disease inherited in a mitochondrial manner. We note that some experts on this panel voted for a classification of pathogenic given the overwhelming evidence of pathogenicity (strong single fiber studies, absent in population databases and present in eight individuals with features of primary mitochondrial disease). This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on August 8, 2022. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS4_moderate, PM2_supporting, PP3, PP1, PS3_supporting -

Diabetes mellitus, noninsulin-dependent, maternally transmitted Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Mar 01, 1998

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
Mitotip	Pathogenic	19
Hmtvar	Pathogenic	0.75

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs199474659; hg19: chrM-3257;