rs199474657

chrM-3243-A-GchrM-3243-A-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.14A>G variant causes a non coding transcript exon change. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Mitomap GenBank: Absent
• Consequence: MT-TL1 ENST00000386347.1 non_coding_transcript_exon
• Scores: Mitotip Uncertain 13
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:35 O:3 MELAS-/-Leigh-Syndrome-/-DMDF-/-MIDD-/-SNHL-/-CPEO-/-MM-/-FSGS-/-ASD-/-Cardiac+multi-organ-dysfunction,MM-/-MELAS-/-SNHL-/-CPEO
• Conservation: PhyloP100: 5.83

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-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/exons	MANE	UniProt
TRNL1	TRNL1.1	n.14A>G		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.14A>G		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.

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:35 Other:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Juvenile myopathy, encephalopathy, lactic acidosis AND stroke Pathogenic:11 Other:1

not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	research	Kids Research, The Children's Hospital at Westmead	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 04, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Pediatric Department, Xiangya Hospital, Central South University	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	May 05, 2021	ACMG classification criteria: PS3 supporting, PS4, PP1 -
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.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 -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 2013	- -
Pathogenic, criteria provided, single submitter	research	HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	Jun 08, 2021	ACMG codes: PS4, PM2, PP1, PP3 -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	-	- 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). -
Pathogenic, criteria provided, single submitter	clinical testing	Johns Hopkins Genomics, Johns Hopkins University	Nov 23, 2021	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Genomic Medicine Lab, University of California San Francisco	Jan 02, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Dec 02, 2021	- -

Mitochondrial disease Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Aug 14, 2023	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. -
Pathogenic, criteria provided, single submitter	clinical testing	New York Genome Center	Nov 02, 2022	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. -
Pathogenic, no assertion criteria provided	research	Donald Williams Parsons Laboratory, Baylor College of Medicine	Jul 31, 2013	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. -
Pathogenic, no assertion criteria provided	clinical testing	Wellcome Centre for Mitochondrial Research, Newcastle University	May 22, 2017	- -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Aug 26, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	May 12, 2017	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). -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -

Diabetes-deafness syndrome maternally transmitted Pathogenic:3

Pathogenic, criteria provided, single submitter	research	Unidad de Genómica Médica UC, Pontificia Universidad Católica de Chile	Mar 05, 2012	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Sep 14, 2022	Criteria applied: PS3,PS4,PP3,PM2_SUP -
Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 01, 2010	- -

Age related macular degeneration 2 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Oct 01, 2010

- -

Sensorineural hearing loss disorder;C0038454:Stroke disorder;C0271650:Glucose intolerance;C0349588:Short stature Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Jan 01, 2017

- -

Cerebral palsy Pathogenic:1

Pathogenic, criteria provided, single submitter

research

Neurogenetics Research Program, University of Adelaide

Jun 10, 2021

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

MERRF/MELAS overlap syndrome Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 01, 2013

- -

not specified Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Institute for Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin

Sep 22, 2022

- -

Auditory neuropathy spectrum disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Department of Otolaryngology, Head and Neck Surgery, Beijing Friendship Hospital, Capital Medical University

Oct 02, 2022

- -

Charcot-Marie-Tooth disease, axonal, mitochondrial form, 1 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

3billion

May 22, 2022

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. -

Mitochondrial complex IV deficiency, nuclear type 1 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 01, 2013

- -

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

- -

Muscle stiffness, painful Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 01, 2013

- -

See cases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Institute of Human Genetics, University Hospital Muenster

Jul 24, 2020

ACMG categories: PP1,PP4,PP5 -

3-methylglutaconic aciduria type 1 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 01, 2013

- -

Cyclical vomiting syndrome Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 01, 2013

- -

LEIGH SYNDROME, MITOCHONDRIAL Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Oct 01, 2010

- -

Hypertrophic cardiomyopathy;C0162671:Juvenile myopathy, encephalopathy, lactic acidosis AND stroke;C0342289:Diabetes-deafness syndrome maternally transmitted;CN230159:Leigh Syndrome (mtDNA mutation) Other:1

not provided, no classification provided

phenotyping only

GenomeConnect - Brain Gene Registry

-

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/. -

Leigh syndrome Other:1

not provided, no classification provided

literature only

GeneReviews

-

- -

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

Other links and lift over

dbSNP: rs199474657; hg19: chrM-3244;