ClinVar Genomic variation as it relates to human health
NC_012920.1(MT-CYB):m.3243A>T
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NC_012920.1(MT-CYB):m.3243A>T
Variation ID: 689856 Accession: VCV000689856.4
- Type and length
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single nucleotide variant, 1 bp
- Location
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MT: 3243 (GRCh38) [ NCBI UCSC ] MT: 3243 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Sep 22, 2019 Mar 26, 2023 Oct 10, 2022 - HGVS
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Nucleotide Protein Molecular
consequenceNC_012920.1:m.3243A>T - Protein change
- Other names
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- Canonical SPDI
- NC_012920.1:3242:A:T
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
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The frequency of the allele represented by this VCV record.
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Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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MT-TL1 | - | - | GRCh38 | 37 | 37 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
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The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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May 4, 2022 | RCV000850688.3 | |
Likely pathogenic (1) |
reviewed by expert panel
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Oct 10, 2022 | RCV003153872.1 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
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The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
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The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
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This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Likely pathogenic
(Oct 10, 2022)
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reviewed by expert panel
Method: curation
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Mitochondrial disease
(Mitochondrial inheritance)
Affected status: unknown
Allele origin:
germline
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ClinGen Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel, ClinGen
Accession: SCV003842281.1
First in ClinVar: Mar 26, 2023 Last updated: Mar 26, 2023 |
Comment:
The m.3243A>T variant in MT-TL1 has been reported in eight unrelated probands with primary mitochondrial disease. Features in affected individuals include mitochondrial encephalomyopathy, lactic acidosis, … (more)
The m.3243A>T variant in MT-TL1 has been reported in eight unrelated probands with primary mitochondrial disease. Features in affected individuals include mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) and chronic progressive external ophthalmoplegia (CPEO), as well as myoclonic epilepsy, exercise intolerance with rhabdomyolysis, cataracts, sensorineural hearing loss, diabetes, peripheral neuropathy, and ataxia (PMIDs: 9168904, 18203188, 20471262, 23220830, 30210801, 33924034, 25504047; PS4_moderate). In all individuals, the variant was present at heteroplasmy, ranging from 69-99% in muscle and 13-50% in blood. Age of onset varied from six to 29 years old. There are no large families reported in the medical literature to consider for evidence of segregation. There are no de novo occurrences of this variant reported to our knowledge. The m.3243A>T variant is absent in the GenBank dataset and gnomAD3.1.2. There is one heteroplasmic occurrence in 195,893 sequences in the Helix database, however the overall frequency is still low (PM2_supporting). The computational predictor MitoTIP suggests this variant is pathogenic, scoring in the 58.8 percentile, and HmtVAR also predicts it to be pathogenic with a score of 0.8 (PP3). The m.3243A>T variant is at the same nucleotide position as a previously established pathogenic variant (m. 3243A>G; PM5_supporting). Several different functional studies have been performed on this variant that support its pathogenicity and show independent deleterious effects of the variant, including generation of cybrids, single fiber testing, and aminoacylation assays (PS3_moderate). Cybrids with high levels of this variant, when compared to wild type, showed lower oxygen consumption, higher glucose consumption and lactate production, increased motility and migration capacities associated with specific glycosylation patterns, lower growth rate, and altered cellular processes (PMIDs: 25504047, 32273537). Single fiber testing showed higher levels of the variant in COX-deficient fibers (95.8 ± 0.7%, n=9) than in COX-positive fibers (44.3 ± 8.8%, n=9; p < 0.001; PMID: 20471262). Structural and aminoacylation studies of in-vitro transcribed human tRNALeu(UUR) showed that the m.3243A>T variant was associated with a 300-fold loss of aminoacylation efficiency (PMID: 12729737). In summary, this variant meets criteria to be classified as likely pathogenic for primary mitochondrial disease inherited in a mitochondrial manner. We note that one expert on this panel felt pathogenic was a more appropriate classification given the functional evidence of impact however the majority agreed with likely pathogenic. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on October 10, 2022. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS4_moderate, PM2_supporting, PP3, PM5_supporting, PS3_moderate. (less)
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Pathogenic
(Jul 12, 2019)
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criteria provided, single submitter
Method: clinical testing
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Juvenile myopathy, encephalopathy, lactic acidosis AND stroke
Affected status: unknown
Allele origin:
germline
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Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine
Accession: SCV000992920.1
First in ClinVar: Sep 22, 2019 Last updated: Sep 22, 2019 |
Comment:
The NC_012920.1:m.3243A>T variant in MT-TL1 gene is interpreted to be a Pathogenic variant based on the modified ACMG guidelines (unpublished). This variant meets the following … (more)
The NC_012920.1:m.3243A>T 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, PM5, PP3 (less)
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Pathogenic
(May 04, 2022)
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criteria provided, single submitter
Method: clinical testing
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Juvenile myopathy, encephalopathy, lactic acidosis AND stroke
Affected status: unknown
Allele origin:
germline
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Mendelics
Accession: SCV002517706.1
First in ClinVar: May 28, 2022 Last updated: May 28, 2022 |
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not provided
(-)
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no classification provided
Method: phenotyping only
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Juvenile myopathy, encephalopathy, lactic acidosis AND stroke
Affected status: yes
Allele origin:
unknown
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GenomeConnect, ClinGen
Accession: SCV003761502.1
First in ClinVar: Feb 07, 2023 Last updated: Feb 07, 2023 |
Comment:
Variant classified as Pathogenic and reported on 08-31-2015 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided … (more)
Variant classified as Pathogenic and reported on 08-31-2015 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. (less)
Clinical Features:
Abnormality of the amniotic fluid (present) , Premature birth (present) , Hypertonia (present) , Generalized hypotonia (present) , Anxiety (present) , Hyperhidrosis (present) , Fragile … (more)
Abnormality of the amniotic fluid (present) , Premature birth (present) , Hypertonia (present) , Generalized hypotonia (present) , Anxiety (present) , Hyperhidrosis (present) , Fragile skin (present) , Hyperextensible skin (present) , Joint hypermobility (present) , Increased susceptibility to fractures (present) , Pectus excavatum (present) , Abnormal esophagus morphology (present) , Abnormal intestine morphology (present) , Recurrent infections (present) (less)
Indication for testing: Diagnostic
Age: 10-19 years
Sex: female
Method: Exome Sequencing
Testing laboratory: GeneDx
Date variant was reported to submitter: 2015-08-31
Testing laboratory interpretation: Pathogenic
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Evaluation of the role of mitochondria in the non-targeted effects of ionizing radiation using cybrid cellular models. | Miranda S | Scientific reports | 2020 | PMID: 32273537 |
Interpretation of mitochondrial tRNA variants. | Wong LC | Genetics in medicine : official journal of the American College of Medical Genetics | 2020 | PMID: 31965079 |
The pathogenic m.3243A>T mitochondrial DNA mutation is associated with a variable neurological phenotype. | Alston CL | Neuromuscular disorders : NMD | 2010 | PMID: 20471262 |
Progressive cerebral vascular degeneration with mitochondrial encephalopathy. | Longo N | American journal of medical genetics. Part A | 2008 | PMID: 18203188 |
Towards understanding human mitochondrial leucine aminoacylation identity. | Sohm B | Journal of molecular biology | 2003 | PMID: 12729737 |
Mitochondrial encephalomyopathy associated with a novel mutation in the mitochondrial tRNA(leu)(UUR) gene (A3243T). | Shaag A | Biochemical and biophysical research communications | 1997 | PMID: 9168904 |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/63fd61ad-6e82-43d1-952a-16c083e6ec90 | - | - | - | - |
Text-mined citations for rs199474657 ...
HelpRecord last updated Dec 09, 2023
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.