chrM-3243-A-G
Variant summary
Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM2PP5_Very_Strong
The ENST00000000000(TRNL1):c.14A>G(p.Glu5Gly) variant causes a missense change. Variant has been reported in ClinVar as Pathogenic (★★★).
Frequency
Consequence
ENST00000000000 missense
Scores
Clinical Significance
Conservation
Publications
- mitochondrial diseaseInheritance: Mitochondrial Classification: LIMITED Submitted by: ClinGen
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ACMG classification
Our verdict: Pathogenic. The variant received 10 ACMG points.
Variant Effect in Transcripts
ACMG analysis was done for transcript: ENST00000386347.1. You can select a different transcript below to see updated ACMG assignments.
RefSeq Transcripts
| Selected | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|
Ensembl Transcripts
| Selected | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| MT-TL1 | ENST00000386347.1 | TSL:6 | n.14A>G | non_coding_transcript_exon | Exon 1 of 1 | ||||
| MT-ND1 | ENST00000361390.2 | TSL:6 | c.-64A>G | upstream_gene | N/A | ENSP00000354687.2 | |||
| MT-RNR2 | ENST00000387347.2 | TSL:6 | n.*14A>G | downstream_gene | N/A |
Frequencies
Mitomap
ClinVar
Submissions by phenotype
MELAS syndrome Pathogenic:15Other:1
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G variant in MT-TL1 gene is interpreted to be a Pathogenic variant based on the modified ACMG guidelines (unpublished).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
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.
- 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).
ACMG classification criteria: PS3 supporting, PS4, PP1
The variant is observed at an extremely low frequency in the gnomAD v4.1.0 dataset (heteroplasmic allele frequency: 0.011%). Predicted Consequence/Location: Mitochondrial variant Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 30962477). The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 17172609, 20697048, 23243073, 23900320, 27296531, 32313153). The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (3billion dataset/ClinVar ID: VCV000009589). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
ACMG codes: PS4, PM2, PP1, PP3
Criteria applied: PS3,PS4,PM5,PP1_MOD,PP3
not provided Pathogenic:6
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).
Mitochondrial disease Pathogenic:6
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.
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.
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.
The m.3243A>G variant in MT-TL1 was reviewed by the Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel as part of the variant pilot for mitochondrial DNA variant specifications (McCormick et al., 2020; PMID: 32906214). This variant has been reported in >16 individuals with primary mitochondrial disease (PS4; PMIDs: 1670860, 2102678, 2268345, 17823937, 23806424, 16682545, 18391161, 9323566, 18294221, 16717204, 12874464, 9285090, 11260383, 30133155, 9323566, 23360351, 10799437, 12221518, 29560378). Clinical syndromes seen in affected individuals include mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS), maternally inherited diabetes and deafness (MIDD), chronic progressive external ophthalmoplegia (CPEO), and Leigh syndrome. Clinical features seen in affected individuals are variable and include myopathy, neuropathy, seizures, hemiparesis, stroke-like episodes, ataxia, dementia, developmental delay and/or regression, headache, migraine, short stature, diabetes, gastrointestinal involvement (dysmotility, reduced appetite, vomiting, dysphagia, constipation, diarrhea), ophthalmoplegia, optic atrophy, retinal dystrophy, ptosis, sensorineural hearing loss, cardiomyopathy, Wolff-Parkinson-White, renal involvement (tubulopathy, focal segmental glomerulosclerosis), mood disorder, lactic acidosis, and ragged red fibers on muscle biopsy. Age of onset ranges from early in life to adulthood. There are several reported de novo occurrences of this variant (PM6_strong; PMIDs: 27331024, 27450679, 11168879). Additionally, this variant segregated with disease in multiple affected members in multiple families and several healthy family members had lower to undetectable levels of the variant (PP1_moderate; PMIDs: 1539604, 8492919, 7931425, 1487758). There are several occurrences of this variant in population databases. The computational predictor MitoTIP suggests this variant is pathogenic (58.8 percentile) and HmtVAR predicts it to be pathogenic with a score of 1 (PP3). Cybrid and single fiber studies support the functional impact of this variant (PMIDs: 18455161, 1378759, 1732728, 8154867, 9741403). In summary, this variant meets criteria to be classified as pathogenic for primary mitochondrial disease inherited in a maternal manner. This classification was approved by the NICHD U24 Mitochondrial Disease Variant Curation Expert Panel as of August 20, 2020. Mitochondrial DNA-specific ACMG/AMP criteria applied: PS4, PM6_strong, PP1_moderate, PP3.
Diabetes-deafness syndrome maternally transmitted Pathogenic:3
Criteria applied: PS3,PS4,PP3,PM2_SUP
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
Sensorineural hearing loss disorder;C0038454:Stroke disorder;C0271650:Glucose intolerance;C0349588:Short stature Pathogenic:1
Maternally-inherited mitochondrial myopathy Pathogenic:1
Variant confirmed as disease-causing by referring clinical team
Cerebral palsy Pathogenic:1
Variant responsible for 80% of MELAS cases (PMID: 2268345).
MERRF/MELAS overlap syndrome Pathogenic:1
not specified Pathogenic:1
Auditory neuropathy spectrum disorder Pathogenic:1
Mitochondrial complex IV deficiency, nuclear type 1 Pathogenic:1
See cases Pathogenic:1
ACMG categories: PP1,PP4,PP5
MELAS syndrome;C0162672:MERRF syndrome Pathogenic:1
3-methylglutaconic aciduria type 1 Pathogenic:1
Cyclical vomiting syndrome Pathogenic:1
Leigh syndrome, mitochondrial Pathogenic:1
Leigh syndrome Other:1
Hypertrophic cardiomyopathy;C0162671:MELAS syndrome;C0342289:Diabetes-deafness syndrome maternally transmitted;CN230159:Leigh Syndrome (mtDNA mutation) Other:1
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
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