rs199474658

Positions:

• chrM-3271-T-C

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2_Supporting PS3_Moderate PS4 PP1_Moderate PP3

This summary comes from the ClinGen Evidence Repository: The m.3271T>C variant in MT-TL1 gene has been reported in more than 40 affected individuals from 20 kindreds (PS4; PMIDs: 1932147, 8482977, 7993661, 8908402, 9766710, 9427220, 11404119, 11828557, 10214753, 12609508, 16006433, 15794182, 16353243, 18206799, 20972245, 25680467, 33951347). The age of onset ranged from early childhood to the late 30s. This variant has been seen in individuals with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS; accounts for approximately 10% of cases of MELAS and is the second most common cause) as well as in one individual with myoclonic epilepsy with ragged red fibers (MERRF). Other features seen in affected individual include muscle weakness, exercise intolerance, fatigue, developmental delay, axonal neuropathy, dementia, migraines, seizures, diabetes, growth hormone deficiency, lipoma, sensorineural hearing loss, hypertrophic cardiomyopathy, Wolff-Parkinson-White arrhythmia, optic atrophy, and short stature. Muscle biopsies showed ragged red fibers, COX-negative fibers, paracrystalline inclusions, hypertrophic/atrophic fibers, enlarged mitochondria, abnormal cristae, increased fat droplets, and variable respiratory chain enzyme activities. Heteroplasmy levels were variable but were highest in muscle and urine, and levels were as high as homoplasmic in muscle. This variant segregated with disease in multiple affected members across several families and several healthy family members had lower levels of the variant (PP1_moderate; PMIDs: 9427220, 16006433, 15794182, 18206799, 25680467). There is one report of a de novo occurrence, however technology at the time could have missed low level variants and the tissue(s) tested was not specified (PMID:11828557). 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 pathogenic (78.3 percentile) and HmtVAR predicts it to be pathogenic score of 0.85 (PP3). Cybrid studies and other assays supported the functional impact of this variant (PS3_moderate; PMIDs: 12527767, 12729737, 15870203, 16120315, 10660592, 9744809, 7603512, 8280119). In summary, this variant meets criteria to be classified as 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 25, 2023. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID:32906214): PS4, PP1_moderate, PM2_supporting, PP3, PS3_moderate. LINK:https://erepo.genome.network/evrepo/ui/classification/CV9590/MONDO:0044970/014

• Frequency: Mitomap GenBank: Absent
• Consequence: MT-TL1 ENST00000386347.1 non_coding_transcript_exon
• Scores: Mitotip Pathogenic 17
• Clinical Significance: Pathogenic reviewed by expert panel P:6 O:1 MELAS-/-DM-/-MERRF-like
• Conservation: PhyloP100: 2.98

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-ND1 (HGNC:7455): (mitochondrially encoded NADH dehydrogenase 1) Enables NADH dehydrogenase (ubiquinone) activity. Involved in mitochondrial electron transport, NADH to ubiquinone and mitochondrial respiratory chain complex I assembly. Located in mitochondrial membrane. Part of mitochondrial respiratory chain complex I. Implicated in several diseases, including MELAS syndrome; neurodegenerative disease (multiple); optic nerve disease (multiple); toxic shock syndrome; and type 2 diabetes mellitus. Biomarker of Alzheimer's disease; Parkinson's disease; and multiple sclerosis. [provided by Alliance of Genome Resources, Apr 2022]

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 10 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.
• PP1: 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
TRNL1	TRNL1.1	n.42T>C		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.42T>C		non_coding_transcript_exon_variant	1/1
MT-ND1	ENST00000361390.2			upstream_gene_variant				ENSP00000354687	P1
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-/-DM-/-MERRF-like

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Juvenile myopathy, encephalopathy, lactic acidosis AND stroke Pathogenic:3 Other:1

not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 04, 2022	- -
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.3271T>C 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 -
Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 01, 2005	- -

not specified Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Mar 17, 2017

- -

Mitochondrial disease Pathogenic:1

Pathogenic, reviewed by expert panel

curation

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

Apr 25, 2023

The m.3271T>C variant in MT-TL1 gene has been reported in more than 40 affected individuals from 20 kindreds (PS4; PMIDs: 1932147, 8482977, 7993661, 8908402, 9766710, 9427220, 11404119, 11828557, 10214753, 12609508, 16006433, 15794182, 16353243, 18206799, 20972245, 25680467, 33951347). The age of onset ranged from early childhood to the late 30s. This variant has been seen in individuals with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS; accounts for approximately 10% of cases of MELAS and is the second most common cause) as well as in one individual with myoclonic epilepsy with ragged red fibers (MERRF). Other features seen in affected individual include muscle weakness, exercise intolerance, fatigue, developmental delay, axonal neuropathy, dementia, migraines, seizures, diabetes, growth hormone deficiency, lipoma, sensorineural hearing loss, hypertrophic cardiomyopathy, Wolff-Parkinson-White arrhythmia, optic atrophy, and short stature. Muscle biopsies showed ragged red fibers, COX-negative fibers, paracrystalline inclusions, hypertrophic/atrophic fibers, enlarged mitochondria, abnormal cristae, increased fat droplets, and variable respiratory chain enzyme activities. Heteroplasmy levels were variable but were highest in muscle and urine, and levels were as high as homoplasmic in muscle. This variant segregated with disease in multiple affected members across several families and several healthy family members had lower levels of the variant (PP1_moderate; PMIDs: 9427220, 16006433, 15794182, 18206799, 25680467). There is one report of a de novo occurrence, however technology at the time could have missed low level variants and the tissue(s) tested was not specified (PMID: 11828557). 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 pathogenic (78.3 percentile) and HmtVAR predicts it to be pathogenic score of 0.85 (PP3). Cybrid studies and other assays supported the functional impact of this variant (PS3_moderate; PMIDs: 12527767, 12729737, 15870203, 16120315, 10660592, 9744809, 7603512, 8280119). In summary, this variant meets criteria to be classified as 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 25, 2023. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS4, PP1_moderate, PM2_supporting, PP3, PS3_moderate. -

Juvenile myopathy, encephalopathy, lactic acidosis AND stroke;C0162672:MERRF syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
Mitotip	Pathogenic	17
Hmtvar	Pathogenic	0.85

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs199474658; hg19: chrM-3272;