M-3243-A-G

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PP5_Very_Strong

Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Mitomap GenBank:
Absent

Consequence

TRNL1
missense

Scores

Mitotip
Uncertain
13

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:38O:3
MELAS-/-Leigh-Syndrome-/-DMDF-/-MIDD-/-SNHL-/-CPEO-/-MM-/-FSGS-/-ASD-/-Cardiac+multi-organ-dysfunction,MM-/-MELAS-/-SNHL-/-CPEO

Conservation

PhyloP100: 5.83
Variant links:
Genes affected
TRNL1 (HGNC:7490): (mitochondrially encoded tRNA leucine 1 (UUA/G)) Implicated in cardiomyopathy. [provided by Alliance of Genome Resources, Apr 2022]
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]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PM2
No frequency data in Mitomap. Probably very rare.
PP5
Variant M-3243-A-G is Pathogenic according to our data. Variant chrM-3243-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 9589.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
TRNL1unassigned_transcript_4788 c.14A>G p.Glu5Gly missense_variant Exon 1 of 1
RNR2unassigned_transcript_4787 n.*14A>G downstream_gene_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt

Frequencies

GnomAD4 exome
Cov.:
0
We have no GnomAD4 genomes data on this position. Probably position not covered by the project.
Gnomad homoplasmic
AF:
0.0
AC:
0
AN:
56383
Gnomad heteroplasmic
AF:
0.00011
AC:
6
AN:
56383

Mitomap

MELAS-/-Leigh-Syndrome-/-DMDF-/-MIDD-/-SNHL-/-CPEO-/-MM-/-FSGS-/-ASD-/-Cardiac+multi-organ-dysfunction,MM-/-MELAS-/-SNHL-/-CPEO

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:38Other:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

MELAS syndrome Pathogenic:12Other:1
Nov 23, 2021
Johns Hopkins Genomics, Johns Hopkins University
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This MT-TL1 variant (rs199474657) is rare (<0.1%) in a large population dataset (gnomAD: 6/56383 total alleles; AF(het)=0.011%); AF(hom)=0.00%) and has been reported in ClinVar and MITOMAP. It is the most common cause of MELAS accounting for about 80 percent of all MELAS cases. m.3243A>G is associated with diverse clinical manifestations (i.e., progressive external ophthalmoplegia, diabetes mellitus, cardiomyopathy, deafness) that collectively constitute a wide phenotypic spectrum ranging from MELAS at the severe end to asymptomatic carrier status at the other end. Factors including random mitochondrial segregation and consequent variable tissue heteroplasmy contribute to the much broader phenotypic spectrum associated with this variant. This MT-TL1 variant results in an A>G change in the D-loop domain of the tRNA, which leads to reduction of mitochondrial DNA (mtDNA)-encoded proteins and oxidative phosphorylation activity. The proportion of m.3243A>G heteroplasmy detected in this patient sample (saliva) was 33.3%. We consider this variant to be pathogenic. -

May 04, 2022
Mendelics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Dec 02, 2021
MGZ Medical Genetics Center
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

-
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- This variant is predicted to result in a nucleotide change from adenine to guanine. - The adenine at this position has high conservation (MITOMASTER). In silico predictions for this variant are consistently pathogenic (MitoTIP, PON-tRNA). - This variant has been previously described as pathogenic in many unrelated individuals with phenotypes including mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS), maternally inherited diabetes and deafness, and progressive external ophthalmoplegia (PMIDs: 11571698 and 23355809). The heteroplasmy level of the variant is correlated with disease burden and progression, where individuals with high heteroplasmy levels tend to have higher disease burden and rate of progression (PMID: 29735722). - Functional studies showed that the variant has a deleterious effect on tRNA structure and function and that this causes defective mitochondrial protein synthesis and reduced mitochondrial energy generation (PMIDs: 10858457, 12101407, 15477592 and 25192935). Additional information: - This variant is heteroplasmic (12.9%). - This gene encodes a mitochondrial tRNA (Leu (UUR)). - This variant is located in the D-loop of the tRNA. - This variant is present in the MITOMAP population database at a frequency of 0.02%. - Inheritance information for this variant is currently unknown. It is not detected in the maternal blood sample (21W001101). -

Jan 01, 2013
OMIM
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: literature only

- -

Jun 08, 2021
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: research

ACMG codes: PS4, PM2, PP1, PP3 -

Jul 12, 2019
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The NC_012920.1:m.3243A>G 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, PP3 -

Jul 03, 2024
Undiagnosed Diseases Network, NIH
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

May 05, 2021
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

ACMG classification criteria: PS3 supporting, PS4, PP1 -

-
Pediatric Department, Xiangya Hospital, Central South University
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

-
GeneReviews
Significance: not provided
Review Status: no classification provided
Collection Method: literature only

- -

-
Kids Research, The Children's Hospital at Westmead
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: research

- -

Jan 02, 2024
Genomic Medicine Lab, University of California San Francisco
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

not provided Pathogenic:5
Sep 07, 2023
Centre for Clinical Genetics and Genomic Diagnostics, Zealand University Hospital
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Aug 26, 2014
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

May 12, 2017
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The m.3243A>G variant (rs199474657) disrupts the mitochondrial tRNA for leucine (UUR), and is one of the most common pathogenic variants in the mitochondrial genome. The clinical presentation associated with this variant is highly variable and depends on the total percentage of abnormal mitochondria and tissue-specific distribution. The m.3243A>G variant was initially identified in patients with mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome (Goto 1990), and recent epidemiological studies found that the most frequent presentation is maternally inherited diabetes and deafness (Mancuso 2013, and Nesbitt 2013). Other clinical manifestations include hypertrophic cardiomyopathy, ataxia, basal-ganglia calcifications, and ophthalmoplegia (Gerbitz 1993 and Majamaa 1998). -

Feb 06, 2024
Clinical Genetics Laboratory, Skane University Hospital Lund
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Oct 23, 2020
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Mitochondrial disease Pathogenic:4
May 22, 2017
Wellcome Centre for Mitochondrial Research, Newcastle University
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Aug 14, 2023
Illumina Laboratory Services, Illumina
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The MT-TL1 m.3243A>G mitochondrial variant has been reported in the literature in a heteroplasmic state in at least 16 individuals with primary mitochondrial disease and is found in approximately 80% of individuals with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) (PMID: 2102678; 2268345; 1715668; 1732728; 27296531; 20301411). The level of heteroplasmy of this variant shows a significant correlation with the clinical signs and symptoms observed in patients and the severity of the clinical presentation (PMID: 27296531). The variant has been identified in a confirmed de novo state in at least four individuals with primary mitochondrial disease (PMID: 27331024; 11168879; 8926502). Cybrid studies support the functional impact of this variant (PMID: 1732728). Multiple lines of computational evidence suggest the variant may have a deleterious effect on gene function. Based on the available evidence, the m.3243A>G variant is classified as pathogenic for primary mitochondrial disease. -

Jul 31, 2013
Donald Williams Parsons Laboratory, Baylor College of Medicine
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: research

This variant has been previously reported as disease-causing. It was an incidental finding in our study, in a 5-year-old female with choroid plexiform carcinoma. There was 23% heteroplasmy detected in blood. -

Nov 02, 2022
New York Genome Center
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The heteroplasmic m.3243A>G variant was detected in 77% of reads in the fetal specimen (amniotic fluid), and detected in 15.8% of reads in the maternal specimen. The m.3243A>G variant is one of the most common pathogenic variants reported in the mitochondrial genome and has been identified in ~80% individuals with MELAS [PMID:20301411], and has also been reported in indiviudals with MIDD, MERRF, and other syndromic and non-syndromic mitochondrial phenotypes (for Review [PMID:36276941]). It is reported in ClinVar as Pathogenic/Likely Pathogenic (VarID:9589) with 29 submissions and no conflicts. The m.3243A>G variant is within the D-loop domain of the mitochondrial tRNA for Leucine (MT-TL1) [PMID: 2102678] and leads to faulty tRNA processing and enzyme maturation (for Review, [PMID:36276941]). The heteroplasmic m.3243A>G variant identified is reported here as Pathogenic. -

Diabetes-deafness syndrome maternally transmitted Pathogenic:3
Oct 01, 2010
OMIM
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: literature only

- -

Sep 14, 2022
Institute of Human Genetics, University of Leipzig Medical Center
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Criteria applied: PS3,PS4,PP3,PM2_SUP -

Mar 05, 2012
Unidad de Genómica Médica UC, Pontificia Universidad Católica de Chile
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: research

Maternally Inherited Diabetes and Deafness (MIDD) is caused by mutations in mitochondrial DNA (mtDNA), mainly m.3243A>G. Severity, onset and clinical phenotype of MIDD patients are partially determined by the proportion of mutant mitochondrial DNA copies in each cell and tissue (heteroplasmy). The identification of MIDD allows a corred treatment with insulin avoiding drugs that may interfere with mitochondrial electron chain transport. We estimated the degree of heteroplasmy of the mutation m.3243A>G from blood, saliva, hair root and a muscle biopsy using quantitative PCR (qPCR) in a female adult patient. For this purpose, PCR products were inserted in a vector creating plasmids with 3243A or G. Mutant and wild-type vectors were mixed in different proportions to create a calibration curve used to interpolate heteroplasmy percentages with qPCR threshold cycles. The proportions of m.3243A>G heteroplasmy were 62% (muscle), 14% (saliva), 6% (blood leukocytes) and 3% in hair root. Quantitative analysis of heteroplasmy showed marked variations in different tissues (highest in muscle and lowest in blood). Given the relatively high heteroplasmy found in saliva, this type of biological sample may represent an adequate non-invasive way for assessing the presence of m.3243A>G mutations in epidemiologic studies. -

Age related macular degeneration 2 Pathogenic:1
Oct 01, 2010
OMIM
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: literature only

- -

Sensorineural hearing loss disorder;C0038454:Stroke disorder;C0271650:Glucose intolerance;C0349588:Short stature Pathogenic:1
Jan 01, 2017
Centre for Mendelian Genomics, University Medical Centre Ljubljana
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Maternally-inherited mitochondrial myopathy Pathogenic:1
Jun 01, 2022
Solve-RD Consortium
Significance: Likely pathogenic
Review Status: no assertion criteria provided
Collection Method: provider interpretation

Variant confirmed as disease-causing by referring clinical team -

Cerebral palsy Pathogenic:1
Jun 10, 2021
Neurogenetics Research Program, University of Adelaide
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: research

Variant responsible for 80% of MELAS cases (PMID: 2268345). -

MERRF/MELAS overlap syndrome Pathogenic:1
Jan 01, 2013
OMIM
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: literature only

- -

not specified Pathogenic:1
Sep 22, 2022
Institute for Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Auditory neuropathy spectrum disorder Pathogenic:1
Oct 02, 2022
Department of Otolaryngology, Head and Neck Surgery, Beijing Friendship Hospital, Capital Medical University
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Mitochondrial complex IV deficiency, nuclear type 1 Pathogenic:1
Jan 01, 2013
OMIM
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: literature only

- -

Charcot-Marie-Tooth disease, axonal, mitochondrial form, 1 Pathogenic:1
May 22, 2022
3billion, Medical Genetics
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

It is observed in the gnomAD v3.1.1 (https://gnomad.broadinstitute.org/) dataset at heteroplasmic allele frequency of 0.011% and is absent as homoplasmy allele. In silico tool predictions suggest damaging effect of the variant on gene or gene product (mitoTIP: 58.80>=50; HmtVAR: 1>0.35). The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (Mitomap PubMed: 2102678, Clinvar ID : VCV000009589.18, PMID: 32554818, 27296531). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -

See cases Pathogenic:1
Jul 24, 2020
Institute of Human Genetics, University Hospital Muenster
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

ACMG categories: PP1,PP4,PP5 -

MELAS syndrome;C0162672:MERRF syndrome Pathogenic:1
Oct 31, 2018
Fulgent Genetics, Fulgent Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

3-methylglutaconic aciduria type 1 Pathogenic:1
Jan 01, 2013
OMIM
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: literature only

- -

Cyclical vomiting syndrome Pathogenic:1
Jan 01, 2013
OMIM
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: literature only

- -

Leigh syndrome, mitochondrial Pathogenic:1
Oct 01, 2010
OMIM
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: literature only

- -

Leigh syndrome Other:1
-
GeneReviews
Significance: not provided
Review Status: no classification provided
Collection Method: literature only

- -

Hypertrophic cardiomyopathy;C0162671:MELAS syndrome;C0342289:Diabetes-deafness syndrome maternally transmitted;CN230159:Leigh Syndrome (mtDNA mutation) Other:1
-
GenomeConnect - Brain Gene Registry
Significance: not provided
Review Status: no classification provided
Collection Method: phenotyping only

Variant interpreted as Pathogenic and reported on 11-20-2013 by Lab GeneDx. Assertions are reported exactly as they appear on the patient provided laboratory report. GenomeConnect does not attempt to reinterpret the variant. The IDDRC-CTSA National Brain Gene Registry (BGR) is a study funded by the U.S. National Center for Advancing Translational Sciences (NCATS) and includes 13 Intellectual and Developmental Disability Research Center (IDDRC) institutions. The study is led by Principal Investigator Dr. Philip Payne from Washington University. The BGR is a data commons of gene variants paired with subject clinical information. This database helps scientists learn more about genetic changes and their impact on the brain and behavior. Participation in the Brain Gene Registry requires participation in GenomeConnect. More information about the Brain Gene Registry can be found on the study website - https://braingeneregistry.wustl.edu/. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
Mitotip
Uncertain
13
Hmtvar
Pathogenic
1.0

Splicing

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs199474657; hg19: chrM-3244; API