ClinVar Genomic variation as it relates to human health
NM_001276345.2(TNNT2):c.851+1G>A
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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NM_001276345.2(TNNT2):c.851+1G>A
Variation ID: 43673 Accession: VCV000043673.17
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 1q32.1 1: 201359622 (GRCh38) [ NCBI UCSC ] 1: 201328750 (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 Feb 28, 2024 Apr 11, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001276345.2:c.851+1G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
splice donor NM_000364.4:c.842+1G>A splice donor NM_001001430.3:c.821+1G>A splice donor NM_001001431.3:c.812+1G>A splice donor NM_001001432.3:c.803+1G>A splice donor NM_001276346.2:c.722+1G>A splice donor NM_001276347.2:c.821+1G>A splice donor NM_001406723.1:c.842+1G>A splice donor NM_001406724.1:c.821+1G>A splice donor NM_001406725.1:c.818+1G>A splice donor NM_001406726.1:c.812+1G>A splice donor NM_001406727.1:c.812+1G>A splice donor NM_001406728.1:c.806+1G>A splice donor NC_000001.11:g.201359622C>T NC_000001.10:g.201328750C>T NG_007556.1:g.23056G>A LRG_431:g.23056G>A LRG_431t1:c.851+1G>A - Protein change
- Other names
- IVS15, G-A, +1
- Canonical SPDI
- NC_000001.11:201359621: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
Help
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
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
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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TNNT2 | No evidence available | No evidence available |
GRCh38 GRCh37 |
898 | 916 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
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
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
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) |
criteria provided, single submitter
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Dec 22, 2014 | RCV000036621.6 | |
Likely pathogenic (2) |
criteria provided, single submitter
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Apr 11, 2023 | RCV001787036.3 | |
Pathogenic (1) |
criteria provided, single submitter
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Sep 24, 2020 | RCV001798106.2 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Apr 11, 2023 | RCV003445106.1 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Apr 11, 2023 | RCV003445107.1 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Nov 23, 2018 | RCV002426558.1 | |
Pathogenic (1) |
criteria provided, single submitter
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Nov 5, 2020 | RCV001233169.6 |
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
Help
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
Help
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
Help
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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Pathogenic
(Dec 22, 2014)
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criteria provided, single submitter
Method: clinical testing
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Hypertrophic cardiomyopathy
Affected status: not provided
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000060276.5
First in ClinVar: May 03, 2013 Last updated: May 29, 2016 |
Comment:
The c.821+1G>A variant in TNNT2 has been reported in one family with HCM, in whi ch it segregated with disease in at least 13 affected … (more)
The c.821+1G>A variant in TNNT2 has been reported in one family with HCM, in whi ch it segregated with disease in at least 13 affected relatives (Thierfelder 199 4, Watkins 1995). The variant has also been identified by our laboratory in one individual with HCM and was absent from large population studies. The c.821+1G>A variant occurs in the invariant region (+/- 1,2) of the splice consensus sequen ce and has been shown to cause altered splicing leading to an abnormal protein ( Watkins 1995, Watkins 1996). In vitro functional studies provide some evidence t hat the abnormal protein has impaired function (Watkins 1996, Mukherjea 1999, Sz czesna 2000, Gafurov 2004). In addition, mouse and zebrafish animal models provi de evidence for a causative role (Tardiff 1998, Becker 2011). In summary, this v ariant meets our criteria to be classified as pathogenic for HCM in an autosomal dominant manner (http://www.partners.org/personalizedmedicine/LMM) based upon s egregation studies, absence from controls and functional evidence. (less)
Number of individuals with the variant: 2
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Pathogenic
(Sep 24, 2020)
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criteria provided, single submitter
Method: clinical testing
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Cardiomyopathy
Affected status: unknown
Allele origin:
germline
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CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario
Accession: SCV002042858.1
First in ClinVar: Jan 01, 2022 Last updated: Jan 01, 2022 |
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Likely pathogenic
(Nov 23, 2018)
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criteria provided, single submitter
Method: clinical testing
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Cardiovascular phenotype
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV002681246.1
First in ClinVar: Nov 29, 2022 Last updated: Nov 29, 2022 |
Comment:
The c.821+1G>A intronic variant results from a G to A substitution one nucleotide after coding exon 14 of the TNNT2 gene. This alteration was identified … (more)
The c.821+1G>A intronic variant results from a G to A substitution one nucleotide after coding exon 14 of the TNNT2 gene. This alteration was identified in a large hypertophic cardiomyopathy family and mRNA analysis demonstrated aberrant splicing (Thierfelder L et al. Cell, 1994 Jun;77:701-12; Watkins H et al. Nat. Genet., 1993 Apr;3:333-7). Based on internal structural analysis, this alteration disrupts part of the C-terminal coiled-coil heptad repeat motif responsible for the interface with TNNI3 (Ambry internal data; Takeda S et al. Nature, 2003 Jul;424:35-41). In vitro and in vivo functional analysis of this variant demonstrated impaired protein function (Watkins H et al. J. Clin. Invest., 1996 Dec;98:2456-61; Tardiff JC et al. J. Clin. Invest., 1998 Jun;101:2800-11; Szczesna D et al. J. Biol. Chem., 2000 Jan;275:624-30; Becker JR et al. Dis Model Mech, 2011 May;4:400-10). This nucleotide position is highly conserved in available vertebrate species. In addition, alterations that disrupt the canonical splice site are expected to cause aberrant splicing resulting in an abnormal protein. Based on the majority of available evidence to date, this variant is likely to be pathogenic. (less)
Number of individuals with the variant: 1
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Pathogenic
(Nov 05, 2020)
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criteria provided, single submitter
Method: clinical testing
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Cardiomyopathy, familial restrictive, 3
Hypertrophic cardiomyopathy 2 Dilated cardiomyopathy 1D
Explanation for multiple conditions: Uncertain.
The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases.
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV001405751.4
First in ClinVar: Jul 16, 2020 Last updated: Feb 28, 2024 |
Comment:
This sequence change falls in intron 15 of the TNNT2 gene. It does not directly change the encoded amino acid sequence of the TNNT2 protein. … (more)
This sequence change falls in intron 15 of the TNNT2 gene. It does not directly change the encoded amino acid sequence of the TNNT2 protein. RNA analysis indicates that this variant induces altered splicing and likely disrupts the C-terminus of the protein. For these reasons, this variant has been classified as Pathogenic. Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Experimental studies have shown that this variant disrupts mRNA splicing (PMID: 8205619). Experimental studies have shown that this variant affects TNNT2 protein function (PMID: 15568820, 27036851, 10617660, 21245263, 9637714, 10850966). This variant has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 8205619, 7898523, 11560853). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 43673). This variant is not present in population databases (ExAC no frequency). (less)
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Likely pathogenic
(Apr 11, 2023)
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criteria provided, single submitter
Method: clinical testing
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Cardiomyopathy, familial restrictive, 3
Affected status: no
Allele origin:
germline
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Genome-Nilou Lab
Accession: SCV004173727.1
First in ClinVar: Dec 09, 2023 Last updated: Dec 09, 2023 |
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Likely pathogenic
(Apr 11, 2023)
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criteria provided, single submitter
Method: clinical testing
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Hypertrophic cardiomyopathy 2
Affected status: no
Allele origin:
germline
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Genome-Nilou Lab
Accession: SCV004173728.1
First in ClinVar: Dec 09, 2023 Last updated: Dec 09, 2023 |
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Likely pathogenic
(Apr 11, 2023)
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criteria provided, single submitter
Method: clinical testing
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Dilated cardiomyopathy 1D
Affected status: no
Allele origin:
germline
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Genome-Nilou Lab
Accession: SCV004173726.1
First in ClinVar: Dec 09, 2023 Last updated: Dec 09, 2023 |
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Pathogenic
(Dec 01, 1996)
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no assertion criteria provided
Method: literature only
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CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 2
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000033468.2
First in ClinVar: Apr 04, 2013 Last updated: Mar 18, 2023 |
Comment on evidence:
In family AU in which Watkins et al. (1993) found that familial hypertrophic cardiomyopathy (CMH2; 115195) was linked to 1q, Thierfelder et al. (1994) found … (more)
In family AU in which Watkins et al. (1993) found that familial hypertrophic cardiomyopathy (CMH2; 115195) was linked to 1q, Thierfelder et al. (1994) found that the clinical disorder was linked to a T-to-C polymorphism at nucleotide 330 of the cDNA of cardiac troponin T. Furthermore, they showed that affected individuals had 2 aberrant splice products. A change from GT to AT in the exon 15 splice donor site resulted in skipping of exon 15 and a shorter cardiac troponin T cDNA. Activation of a cryptic splice site in intron 15 caused the insertion of the first 13 nucleotides of intron 15 into the cDNA sequence and resulted in the longer product. The mutation was identified in all affected adults in family AU and in 3 clinically unaffected adults who were known to carry the disease haplotype at multiple polymorphic markers. It was not present in other clinically unaffected adults or in over 200 chromosomes 1 derived from unrelated normal individuals. The other mutations in the TNNT2 gene and in alpha-tropomyosin that had been demonstrated as causes of CMH were missense mutations. This mutation is expected to cause a truncated TnT peptide lacking the conserved C terminus. Watkins et al. (1996) devised a series of experiments designed to test whether the mutated TNNT2 functioned as a null allele or produced a 'poison peptide.' The missense mutations all result in altered polypeptides which, after they incorporate into the sarcomere, are dominant over the normal protein encoded by the remaining, wildtype allele. Watkins et al. (1996) used a quail myoblast-to-myotube system in which the mutant cardiac troponin was expressed and thereby determined the functional consequences. The data showed that the mutated gene is not a null allele but rather produces a stable, truncated polypeptide that accumulates in the myotube and is subsequently incorporated into the sarcomere. This protein displayed a dominant-negative effect on sarcomeric function, as evidenced by greatly diminished force production, even when it was coexpressed with the wildtype sequence. (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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Mutations in troponin T associated with Hypertrophic Cardiomyopathy increase Ca(2+)-sensitivity and suppress the modulation of Ca(2+)-sensitivity by troponin I phosphorylation. | Messer AE | Archives of biochemistry and biophysics | 2016 | PMID: 27036851 |
Human cardiomyopathy mutations induce myocyte hyperplasia and activate hypertrophic pathways during cardiogenesis in zebrafish. | Becker JR | Disease models & mechanisms | 2011 | PMID: 21245263 |
Aberrant 5' splice sites in human disease genes: mutation pattern, nucleotide structure and comparison of computational tools that predict their utilization. | Buratti E | Nucleic acids research | 2007 | PMID: 17576681 |
The Delta 14 mutation of human cardiac troponin T enhances ATPase activity and alters the cooperative binding of S1-ADP to regulated actin. | Gafurov B | Biochemistry | 2004 | PMID: 15568820 |
Structure of the core domain of human cardiac troponin in the Ca(2+)-saturated form. | Takeda S | Nature | 2003 | PMID: 12840750 |
Hypertrophic cardiomyopathy: histopathological features of sudden death in cardiac troponin T disease. | Varnava AM | Circulation | 2001 | PMID: 11560853 |
Investigation of a truncated cardiac troponin T that causes familial hypertrophic cardiomyopathy: Ca(2+) regulatory properties of reconstituted thin filaments depend on the ratio of mutant to wild-type protein. | Redwood C | Circulation research | 2000 | PMID: 10850966 |
Altered regulation of cardiac muscle contraction by troponin T mutations that cause familial hypertrophic cardiomyopathy. | Szczesna D | The Journal of biological chemistry | 2000 | PMID: 10617660 |
Altered regulatory function of two familial hypertrophic cardiomyopathy troponin T mutants. | Mukherjea P | Biochemistry | 1999 | PMID: 10529204 |
A truncated cardiac troponin T molecule in transgenic mice suggests multiple cellular mechanisms for familial hypertrophic cardiomyopathy. | Tardiff JC | The Journal of clinical investigation | 1998 | PMID: 9637714 |
Statistical features of human exons and their flanking regions. | Zhang MQ | Human molecular genetics | 1998 | PMID: 9536098 |
Expression and functional assessment of a truncated cardiac troponin T that causes hypertrophic cardiomyopathy. Evidence for a dominant negative action. | Watkins H | The Journal of clinical investigation | 1996 | PMID: 8958207 |
Mutations in the genes for cardiac troponin T and alpha-tropomyosin in hypertrophic cardiomyopathy. | Watkins H | The New England journal of medicine | 1995 | PMID: 7898523 |
Alpha-tropomyosin and cardiac troponin T mutations cause familial hypertrophic cardiomyopathy: a disease of the sarcomere. | Thierfelder L | Cell | 1994 | PMID: 8205619 |
A disease locus for familial hypertrophic cardiomyopathy maps to chromosome 1q3. | Watkins H | Nature genetics | 1993 | PMID: 7981753 |
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Text-mined citations for rs111377893 ...
HelpRecord last updated Mar 05, 2024
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.