Submissions for variant NC_012920.1:m.3243A>G

dbSNP: rs199474657

Total submissions: 35

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000224855	SCV000280725	pathogenic	not provided	2014-08-26	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000224855	SCV000605443	pathogenic	not provided	2017-05-12	criteria provided, single submitter	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).
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000626561	SCV000747262	pathogenic	Sensorineural hearing loss disorder; Short stature; Glucose intolerance; Stroke disorder	2017-01-01	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000763623	SCV000894487	pathogenic	MERRF syndrome; Juvenile myopathy, encephalopathy, lactic acidosis AND stroke	2018-10-31	criteria provided, single submitter	clinical testing
Unidad de Genómica Médica UC, Pontificia Universidad Católica de Chile	RCV000032997	SCV000899115	pathogenic	Diabetes-deafness syndrome maternally transmitted	2012-03-05	criteria provided, single submitter	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.
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine	RCV000010206	SCV000992919	pathogenic	Juvenile myopathy, encephalopathy, lactic acidosis AND stroke	2019-07-12	criteria provided, single submitter	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
Kids Research, The Children's Hospital at Westmead	RCV000010206	SCV001244729	pathogenic	Juvenile myopathy, encephalopathy, lactic acidosis AND stroke		criteria provided, single submitter	research
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000224855	SCV001447493	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Neurogenetics Research Program, University of Adelaide	RCV001794441	SCV001737599	pathogenic	Cerebral palsy	2021-06-10	criteria provided, single submitter	research	Variant responsible for 80% of MELAS cases (PMID: 2268345).
Johns Hopkins Genomics, Johns Hopkins University	RCV000010206	SCV002051777	pathogenic	Juvenile myopathy, encephalopathy, lactic acidosis AND stroke	2021-11-23	criteria provided, single submitter	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.
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	RCV000010206	SCV002103151	pathogenic	Juvenile myopathy, encephalopathy, lactic acidosis AND stroke	2021-06-08	criteria provided, single submitter	research	ACMG codes: PS4, PM2, PP1, PP3
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV000010206	SCV002512725	likely pathogenic	Juvenile myopathy, encephalopathy, lactic acidosis AND stroke	2021-05-05	criteria provided, single submitter	clinical testing	ACMG classification criteria: PS3 supporting, PS4, PP1
Mendelics	RCV000010206	SCV002517705	pathogenic	Juvenile myopathy, encephalopathy, lactic acidosis AND stroke	2022-05-04	criteria provided, single submitter	clinical testing
3billion	RCV002250458	SCV002521380	likely pathogenic	Charcot-Marie-Tooth disease, axonal, mitochondrial form, 1	2022-05-22	criteria provided, single submitter	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.
Institute for Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin	RCV002285005	SCV002574881	pathogenic	not specified	2022-09-22	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV000032997	SCV002576462	pathogenic	Diabetes-deafness syndrome maternally transmitted	2022-09-14	criteria provided, single submitter	clinical testing	Criteria applied: PS3,PS4,PP3,PM2_SUP
Institute of Human Genetics, University Hospital Muenster	RCV002287327	SCV002577758	pathogenic	See cases	2020-07-24	criteria provided, single submitter	clinical testing	ACMG categories: PP1,PP4,PP5
MGZ Medical Genetics Center	RCV000010206	SCV002579722	pathogenic	Juvenile myopathy, encephalopathy, lactic acidosis AND stroke	2021-12-02	criteria provided, single submitter	clinical testing
Pediatric Department, Xiangya Hospital, Central South University	RCV000010206	SCV002761207	pathogenic	Juvenile myopathy, encephalopathy, lactic acidosis AND stroke		criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000010206	SCV003921833	pathogenic	Juvenile myopathy, encephalopathy, lactic acidosis AND stroke		criteria provided, single submitter	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).
Illumina Laboratory Services, Illumina	RCV000495738	SCV004101341	pathogenic	Mitochondrial disease	2023-08-14	criteria provided, single submitter	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.
OMIM	RCV000010206	SCV000030429	pathogenic	Juvenile myopathy, encephalopathy, lactic acidosis AND stroke	2013-01-01	no assertion criteria provided	literature only
OMIM	RCV000010208	SCV000030431	pathogenic	Muscle stiffness, painful	2013-01-01	no assertion criteria provided	literature only
OMIM	RCV000010209	SCV000030433	pathogenic	Age related macular degeneration 2	2013-01-01	no assertion criteria provided	literature only
OMIM	RCV000010210	SCV000030434	pathogenic	Cyclical vomiting syndrome	2013-01-01	no assertion criteria provided	literature only
OMIM	RCV000010211	SCV000030435	pathogenic	Cytochrome-c oxidase deficiency disease	2013-01-01	no assertion criteria provided	literature only
OMIM	RCV000022901	SCV000044192	pathogenic	3-methylglutaconic aciduria type 1	2013-01-01	no assertion criteria provided	literature only
OMIM	RCV000022902	SCV000044193	pathogenic	MERRF/MELAS overlap syndrome	2013-01-01	no assertion criteria provided	literature only
OMIM	RCV000032997	SCV000056776	pathogenic	Diabetes-deafness syndrome maternally transmitted	2013-01-01	no assertion criteria provided	literature only
GeneReviews	RCV000143997	SCV000188883	not provided	Leigh syndrome		no assertion provided	literature only
Wellcome Centre for Mitochondrial Research, Newcastle University	RCV000495738	SCV000577894	pathogenic	Mitochondrial disease	2017-05-22	no assertion criteria provided	clinical testing
Donald Williams Parsons Laboratory, Baylor College of Medicine	RCV000495738	SCV000599945	pathogenic	Mitochondrial disease	2013-07-31	no assertion criteria provided	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.
GenomeConnect - Brain Gene Registry	RCV003325938	SCV004032177	not provided	Diabetes-deafness syndrome maternally transmitted; Juvenile myopathy, encephalopathy, lactic acidosis AND stroke; Hypertrophic cardiomyopathy; Leigh Syndrome (mtDNA mutation)		no assertion provided	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/.
GeneReviews	RCV000010206	SCV004042618	not provided	Juvenile myopathy, encephalopathy, lactic acidosis AND stroke		no assertion provided	literature only
Department of Otolaryngology, Head and Neck Surgery, Beijing Friendship Hospital, Capital Medical University	RCV003984803	SCV004801112	pathogenic	Auditory neuropathy spectrum disorder	2022-10-02	no assertion criteria provided	clinical testing