ClinVar Genomic variation as it relates to human health
m.3303C>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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m.3303C>T
Variation ID: 9592 Accession: VCV000009592.4
- Type and length
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single nucleotide variant, 1 bp
- Location
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MT: 3303 (GRCh38) [ NCBI UCSC ] MT: 3303 (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 Apr 4, 2013 Apr 15, 2023 Jan 9, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNC_012920.1:m.3303C>T - Protein change
- Other names
- 3303C-T
- Canonical SPDI
- NC_012920.1:3302:C: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
Help
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 (1) |
no assertion criteria provided
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Aug 1, 1999 | RCV000010215.2 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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May 4, 2022 | RCV000850713.2 | |
Likely pathogenic (1) |
reviewed by expert panel
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Jan 9, 2023 | RCV003162234.1 |
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
(Jan 09, 2023)
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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: SCV003915442.1
First in ClinVar: Apr 15, 2023 Last updated: Apr 15, 2023 |
Comment:
The m.3303C>T variant in MT-TL1 has been reported in at least 16 unrelated individuals with primary mitochondrial disease (PS4; 13 individuals were reported in the … (more)
The m.3303C>T variant in MT-TL1 has been reported in at least 16 unrelated individuals with primary mitochondrial disease (PS4; 13 individuals were reported in the medical literature, PMIDs: 23847141, 10431114, 32167396, 11768589, 33013660, 20226758, 23258140, 7906985, 31965079; an additional three cases were known to members of this Expert Panel). Many affected individuals had hypertrophic cardiomyopathy and/or skeletal myopathy, as well as exercise intolerance, muscle weakness, lactic acidosis, and failure to thrive. Age of onset varied from infancy to adulthood. Heteroplasmy levels in affected individuals ranged from 58-97% in muscle, 20-80% in blood, and, in one case, was almost homoplasmic in fibroblasts. There are no de novo occurrences of this variant to our knowledge. 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; PMID: 10431114, also seen in cases known to Expert Panel members). Of note, there is a report of this variant in individuals with premature ovarian insufficiency (POI, PMID: 30404982), however this Expert Panel agreed this presentation, when isolated, is not known to be associated with mitochondrial DNA etiologies and it is not clear other organ systems were or were not screened in these cases. Therefore, these cases were not considered as supporting evidence for this variant classification. There is one occurrence in population databases as one individual in the Helix dataset had this variant present at heteroplasmy. Although there is one occurrence, the frequency is still low (PM2_supporting). The computational predictor MitoTIP suggests this variant is pathogenic (92.7 percentile) and HmtVAR predicts it to be pathogenic score of 0.65 (PP3). Single fiber testing (PMID: 11271374) showed higher levels of the variant in ragged red fibers that were COX-negative (42.4±7.0%) and in ragged red fibers that were COX-positive (58.2±5.8%), and this was significantly higher than levels of the variant in normal appearing fibers (10.7±6.3%; PS3_supporting). Of note, cybrid studies are reported however the generated cybrids include other mitochondrial DNA variants precluding consideration as evidence of pathogenicity of this variant only (PMID: 30404982). In summary, this variant meets criteria to be classified as likely pathogenic for primary mitochondrial disease inherited in a mitochondrial manner. We note, however, that some members of this Expert Panel elected to modify the classification to pathogenic given the extent of cases from different ethnic backgrounds that have been reported with overlapping phenotypes that is further supported by the evidence outlined above. The experts were almost evenly divided on the final classification as five experts voted to keep the classification as likely pathogenic and four voted for pathogenic. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on January 9, 2023. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS4, PP1_moderate, PM2_supporting, PP3, PS3_supporting. (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: SCV000992946.1
First in ClinVar: Sep 22, 2019 Last updated: Sep 22, 2019 |
Comment:
The NC_012920.1:m.3303C>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.3303C>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: PS5, PM7, PM9, PM10 (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: SCV002517714.1
First in ClinVar: May 28, 2022 Last updated: May 28, 2022 |
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Pathogenic
(Aug 01, 1999)
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no assertion criteria provided
Method: literature only
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CARDIOMYOPATHY WITH OR WITHOUT SKELETAL MYOPATHY
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000030439.1
First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013 |
Comment on evidence:
Silvestri et al. (1994) described a C-to-T transition at nucleotide 3303 of mtDNA in 7 members of a family with cardiomyopathy and myopathy. The proband … (more)
Silvestri et al. (1994) described a C-to-T transition at nucleotide 3303 of mtDNA in 7 members of a family with cardiomyopathy and myopathy. The proband and 2 sibs had fatal infantile cardiomyopathy, whereas in 3 maternal relatives the disease manifested later in life as sudden cardiac death or as mitochondrial myopathy with cardiomyopathy. The mutation was homoplasmic in all tissues (including blood) from the proband and her brother, but heteroplasmic in blood from 5 oligosymptomatic or asymptomatic maternal relatives. The mutation disrupted a conserved basepair in the aminoacyl stem of the tRNA-leu (UUR). The causative role of the 3303C-T mutation in the MTTL1 gene was confirmed by Bruno et al. (1999), who found the mutation in 8 patients from 4 unrelated families. In the first family, the clinical presentation was infantile cardiomyopathy; in the second family, proximal limb and neck weakness dominated the clinical picture for the first 10 years of life, when cardiac dysfunction became apparent; in the third family, 2 individuals presented with isolated skeletal myopathy and 2 others with skeletal myopathy and cardiomyopathy; in the fourth family, 1 patient had fatal infantile cardiomyopathy and the other had a combination of skeletal myopathy and cardiomyopathy. (less)
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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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Interpretation of mitochondrial tRNA variants. | Wong LC | Genetics in medicine : official journal of the American College of Medical Genetics | 2020 | PMID: 31965079 |
The mitochondrial DNA C3303T mutation can cause cardiomyopathy and/or skeletal myopathy. | Bruno C | The Journal of pediatrics | 1999 | PMID: 10431114 |
Maternally inherited mitochondrial cardiomyopathy associated with a C-to-T transition at nucleotide 3303 of mitochondrial DNA in the tRNA(Leu(UUR)) gene. | Goldstein JD | Pediatric and developmental pathology : the official journal of the Society for Pediatric Pathology and the Paediatric Pathology Society | 1999 | PMID: 9841711 |
A new mtDNA mutation in the tRNA(Leu(UUR)) gene associated with maternally inherited cardiomyopathy. | Silvestri G | Human mutation | 1994 | PMID: 7906985 |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/ee0df17b-14b1-4758-bc28-e654835600fe | - | - | - | - |
Text-mined citations for rs199474660 ...
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.