ClinVar Genomic variation as it relates to human health
NM_001276345.2(TNNT2):c.305G>T (p.Arg102Leu)
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.305G>T (p.Arg102Leu)
Variation ID: 235063 Accession: VCV000235063.3
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 1q32.1 1: 201365297 (GRCh38) [ NCBI UCSC ] 1: 201334425 (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 Jun 3, 2016 Jun 3, 2016 Jan 18, 2012 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001276345.2:c.305G>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001263274.1:p.Arg102Leu missense NM_000364.4:c.305G>T NP_000355.2:p.Arg102Leu missense NM_001001430.3:c.275G>T NP_001001430.1:p.Arg92Leu missense NM_001001431.3:c.275G>T NP_001001431.1:p.Arg92Leu missense NM_001001432.3:c.260G>T NP_001001432.1:p.Arg87Leu missense NM_001276346.2:c.291+313G>T intron variant NM_001276347.2:c.275G>T NP_001263276.1:p.Arg92Leu missense NC_000001.11:g.201365297C>A NC_000001.10:g.201334425C>A NG_007556.1:g.17381G>T LRG_431:g.17381G>T LRG_431t1:c.305G>T LRG_431p1:p.Arg102Leu - Protein change
- R102L, R92L, R87L
- Other names
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- Canonical SPDI
- NC_000001.11:201365296:C:A
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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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TNNT2 | No evidence available | No evidence available |
GRCh38 GRCh37 |
946 | 964 |
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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Jan 18, 2012 | RCV000223821.3 |
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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Pathogenic
(Jan 18, 2012)
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no assertion criteria provided
Method: clinical testing
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Not provided
Affected status: not provided
Allele origin:
germline
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Stanford Center for Inherited Cardiovascular Disease, Stanford University
Accession: SCV000280517.1
First in ClinVar: Jun 03, 2016 Last updated: Jun 03, 2016 |
Comment:
Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case … (more)
Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. TNNT2 Arg92Leu (R92L; at the nucleotide level) The variant has been reported in at least 3 unrelated cases of HCM with moderate segregation data in one family and strong functional data available both in vitro and in a transgenic mouse model. Varnava et al. (2001) detected Arg92Leu in one case of HCM. Some papers appear to list this variant as “Arg102Leu”: Forissier et al. (1996) first reported “Arg102Leu” in a French family, where it segregated with disease in 4 family members (two affected sisters, who each had an affected child). Richard et al. (2003) found it in one HCM patient recruited in France Two other mutations at the same codon have also been reported in families with HCM: p.Arg92Trp, which we categorize as very likely disease causing, and p.Arg92Gln, which we categorize as very likely disease causing. Variation at nearby loci of TNNT2 (within 10 amino acids to either side) has been associated with disease, supporting the functional importance of this region of the protein. These HCM variants include Glu83Lys, Val85Leu, Asp86Ala, Arg94Leu, Arg94Cys, and Lys97Asn (Willott et al. 2010; Harvard Sarcomere Protein Gene Mutation Database). The region between residues ~80-180 of TNNT2 has been described as essential for anchoring the troponin-tropomyosin complex to the thin filament (Hinkle et al. 1999, Palm et al. 2001). In vitro functional data from Palm et al. (2001) suggests that a change at codon 92—whether Arg92Trp, Arg92Gln or Arg92Leu—impairs binding of troponin T to tropomyosin and makes the protein less effective at promoting the binding of tropomyosin to actin. Harada & Potter (2004) showed the variant to alter the contractile properties of skinned cardiac fibers, including the response of cardiac contraction to changes in pH. Haim et al. (2007) showed altered calcium handling in isolated myocytes from transgenic Arg94Leu mice. He et al. (2007) showed that transgenic mice bearing the Arg92Trp or Arg92Leu mutation had a greater “energy cost” for cardiac muscle contraction than wild-type mice. The magnitude of these changes was mutation-specific: Arg92Trp hearts showed more severe energetic abnormalities and greater contractile dysfunction than Arg92Leu hearts. Guinto et al. (2009) showed diastolic dysfunction in transgenic mice carrying the variant, and altered calcium kinetics in isolated transgenic myocytes. This is a nonconservative amino acid change from a basic, positively-charged Arginine to a nonpolar Leucine. The Arginine at codon 92 is highly conserved across 39 vertebrate species examined (it is a Lysine in medaka) and surrounding residues are also highly conserved. In silico analysis with PolyPhen-2 (http://genetics.bwh.harvard.edu/pph2/) predicts the variant to be “probably damaging”. In total the variant has not been seen in ~5540 published controls and publicly available population datsets. There is no variation at codon 92 listed in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~3500 Caucasian and ~1800 African American individuals (as of 1/15/2012). There is also no variation at this codon listed in dbSNP or 1000 genomes (as of 1/15/2012). The variant was not observed in published controls: Forissier et al. (1996) did not find it in 50 controls. Varnava et al. (2001) did not detect it in at least 90 control individuals. Richard et al. (2003) did not find the variant in 100 (European?) controls. (less)
Number of individuals with the variant: 3
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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
HelpThere are no citations for germline classification of this variant in ClinVar. If you know of citations for this variation, please consider submitting that information to ClinVar. |
Text-mined citations for rs121964856 ...
HelpRecord last updated Mar 11, 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.