ClinVar Genomic variation as it relates to human health
NC_012920.1(MT-TL1):m.3258T>C
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-TL1):m.3258T>C
Variation ID: 986454 Accession: VCV000986454.2
- Type and length
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single nucleotide variant, 1 bp
- Location
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MT: 3258 (GRCh38) [ NCBI UCSC ] MT: 3258 (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 Oct 15, 2022 Nov 11, 2023 Aug 8, 2022 - HGVS
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Nucleotide Protein Molecular
consequenceNC_012920.1:m.3258T>C - Protein change
- Other names
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- Canonical SPDI
- NC_012920.1:3257:T:C
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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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Likely pathogenic (2) |
reviewed by expert panel
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Aug 8, 2022 | RCV002291221.2 |
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
(Aug 08, 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: SCV002583529.1
First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022 |
Comment:
The m.3258T>C variant in MT-TL1 has been reported in at least three probands to date. The first case report was a young adult with severe … (more)
The m.3258T>C variant in MT-TL1 has been reported in at least three probands to date. The first case report was a young adult with severe hyperlactatemia associated with mild exercise intolerance and mild lipidosis. This individual had a combined respiratory chain deficiency in liver with normal activities in muscle. This proband’s mother died in early adulthood from an unexplained cause The variant was listed as being heteroplasmic but the levels were not reported (PMID: 11335700). The second case was a young adult with MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes) characterized by fatigue, acidosis, hyperCKemia, stroke-like episodes, and tonic clonic seizures; with ragged red fibers and COX negative fibers on muscle biopsy. The variant was present at 96% in muscle and 57% in blood (PMID:?12798797). The third case was younger at presentation with neurological involvement (ataxia, regression, myoclonic epilepsy) as well as decreased complex I and IV activities in muscle, increased lactate in blood and CSF, and a normal brain MRI. Heteroplasmy levels were not provided (PMID: 23847141). Haplogroup information was not reported for all cases however given the features and biochemistry reported in these cases, this Expert Panel agreed to consider them as a supporting line of evidence (PS4_supporting). The variant segregated with features of primary mitochondrial disease and unaffected status in three family members from one family. The variant was present at 96% in muscle and 57% in blood in the proband whereas in her healthy mother had the variant at 19% in blood, one healthy brother had the variant at 30% in blood, and another healthy brother had the variant at 48% in blood (PP1; PMID:12798797). There is one occurrence of this variant in GenBank dataset, however this is from an individual with known mitochondrial disease. This variant is absent in gnomAD v3.1.2 and in Helix dataset therefore this variant is absent in healthy individuals (PM2_supporting). The computational predictor MitoTIP suggests this variant impacts the function of this tRNA with a score of 82.6%, as does HmtVar with a score of 0.8 (PP3). Single fiber analysis in muscle showed that the ragged red fiber had extremely high levels of variant (n = 7; 99.4% +/- 0.9%), whereas normal muscle fibers had significantly lower levels (n = 8; 90.1 +/- 5.1%; P < 0:05, Mann–Whitney’s U-test) (PS3_supporting, PMID: 12798797). In summary, this variant meets criteria to be classified as uncertain significance however, after extensive discussion, this Expert Panel elected to modify the classification to likely pathogenic given the evidence shown in single fibers studies for this variant and because the phenotype reported in these cases is consistent with mitochondrial tRNA-related diseases. This classification was approved by the NICHD/NINDS U24 Mitochondrial Disease Variant Curation Expert Panel on August 8, 2022. Mitochondrial DNA-specific ACMG/AMP criteria applied: PM2_supporting, PP1, PP3, PS4_supporting, PS3_supporting. (less)
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Likely pathogenic
(Jul 27, 2023)
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criteria provided, single submitter
Method: clinical testing
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Mitochondrial disease
Affected status: unknown
Allele origin:
unknown
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Illumina Laboratory Services, Illumina
Accession: SCV004101288.1
First in ClinVar: Nov 11, 2023 Last updated: Nov 11, 2023 |
Comment:
The MT-TL1 m.3258T>C mitochondrial variant results in the substitution of thymidine at mitochondrial nucleotide position m.3258 with cytosine. This variant has been previously identified in … (more)
The MT-TL1 m.3258T>C mitochondrial variant results in the substitution of thymidine at mitochondrial nucleotide position m.3258 with cytosine. This variant has been previously identified in three individuals with a phenotype consistent with primary mitochondrial disease (PMID: 11335700; PMID:12798797; PMID:23847141). A single-fiber study conducted using patient muscle tissue demonstrated a correlation between mitochondrial respiration and variant heteroplasmy (PMID: 12798797). This variant has been shown to segregate with disease in an affected family, with lower heteroplasmy levels associated with unaffected status (PMID: 12798797). This variant is not observed at a significant frequency in version 3.1.2 of the Genome Aggregation Database or in MITOMAP. Multiple lines of computational evidence suggest the variant may impact the gene or gene product. Based on the available evidence, the m.3258T>C variant is classified as likely pathogenic for primary mitochondrial disease. (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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Prevalence of rare mitochondrial DNA mutations in mitochondrial disorders. | Bannwarth S | Journal of medical genetics | 2013 | PMID: 23847141 |
Two pathogenic mutations in the mitochondrial DNA tRNA Leu(UUR) gene (T3258C and A3280G) resulting in variable clinical phenotypes. | Campos Y | Neuromuscular disorders : NMD | 2003 | PMID: 12798797 |
Mitochondrial DNA transfer RNA gene sequence variations in patients with mitochondrial disorders. | Sternberg D | Brain : a journal of neurology | 2001 | PMID: 11335700 |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/a964d051-bdd1-4776-8f6e-d0fbf6dcd0b4 | - | - | - | - |
Text-mined citations for this variant ...
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.