ClinVar Genomic variation as it relates to human health
NM_001276345.2(TNNT2):c.260C>T (p.Pro87Leu)
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.260C>T (p.Pro87Leu)
Variation ID: 43619 Accession: VCV000043619.24
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 1q32.1 1: 201365644 (GRCh38) [ NCBI UCSC ] 1: 201334772 (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 Dec 6, 2014 Oct 8, 2024 Feb 5, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001276345.2:c.260C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001263274.1:p.Pro87Leu missense NM_000364.4:c.260C>T NP_000355.2:p.Pro87Leu missense NM_001001430.3:c.230C>T NP_001001430.1:p.Pro77Leu missense NM_001001431.3:c.230C>T NP_001001431.1:p.Pro77Leu missense NM_001001432.3:c.215C>T NP_001001432.1:p.Pro72Leu missense NM_001276346.2:c.257C>T NP_001263275.1:p.Pro86Leu missense NM_001276347.2:c.230C>T NP_001263276.1:p.Pro77Leu missense NC_000001.11:g.201365644G>A NC_000001.10:g.201334772G>A NG_007556.1:g.17034C>T LRG_431:g.17034C>T LRG_431t1:c.260C>T LRG_431p1:p.Pro87Leu - Protein change
- P77L, P87L, P86L, P72L
- Other names
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- Canonical SPDI
- NC_000001.11:201365643:G: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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The Genome Aggregation Database (gnomAD) 0.00002
Exome Aggregation Consortium (ExAC) 0.00003
The Genome Aggregation Database (gnomAD), exomes 0.00004
Trans-Omics for Precision Medicine (TOPMed) 0.00004
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008
- Links
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
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 |
958 | 977 |
Conditions - Germline
Condition
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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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Uncertain significance (1) |
criteria provided, single submitter
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Oct 3, 2012 | RCV000036563.5 | |
Uncertain significance (1) |
no assertion criteria provided
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Jun 1, 2014 | RCV000148902.3 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Sep 23, 2022 | RCV000646057.7 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Feb 5, 2024 | RCV001185063.6 | |
Uncertain significance (3) |
criteria provided, single submitter
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Oct 20, 2020 | RCV001588848.5 | |
Uncertain significance (1) |
criteria provided, single submitter
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Apr 11, 2023 | RCV003450669.1 | |
Uncertain significance (1) |
criteria provided, single submitter
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Apr 11, 2023 | RCV003450670.1 | |
Uncertain significance (1) |
criteria provided, single submitter
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Apr 11, 2023 | RCV003450671.1 | |
Uncertain significance (1) |
criteria provided, single submitter
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Dec 7, 2021 | RCV004018795.1 | |
TNNT2-related disorder
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Uncertain significance (1) |
no assertion criteria provided
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Jul 26, 2024 | RCV004737176.1 |
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
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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Uncertain significance
(Oct 20, 2020)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV001822892.1
First in ClinVar: Sep 08, 2021 Last updated: Sep 08, 2021 |
Comment:
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 33025817, … (more)
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 33025817, 23299917, 19914256, 11560853, 20530761, 25637381) (less)
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Uncertain significance
(Oct 03, 2012)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: not provided
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000060218.6
First in ClinVar: May 03, 2013 Last updated: Jan 31, 2015 |
Comment:
The Pro77Leu variant in TNNT2 has been identified in 1 individual with HCM/SCD ( Varnava 2001) as well as in 1/8600 European American chromosomes from … (more)
The Pro77Leu variant in TNNT2 has been identified in 1 individual with HCM/SCD ( Varnava 2001) as well as in 1/8600 European American chromosomes from a broad po pulation by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS /; dbSNP rs144900708). Proline (Pro) at position 77 is conserved in mammals and some evolutionarily distant species, but frog and stickleback carry a leucine (L eu; this variant) at this position suggesting that this change may be tolerated. Other computational analyses (biochemical amino acid properties, AlignGVGD, Pol yPhen2, and SIFT) suggest that this variant may not impact the protein, though t his information is not predictive enough to rule out pathogenicity. Additional s tudies are needed to fully assess the clinical significance of this variant. (less)
Number of individuals with the variant: 1
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Uncertain significance
(Sep 08, 2021)
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criteria provided, single submitter
Method: clinical testing
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Hypertrophic cardiomyopathy 2
Dilated cardiomyopathy 1D Cardiomyopathy, familial restrictive, 3
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV002784510.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Uncertain significance
(Sep 23, 2022)
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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
Affected status: unknown
Allele origin:
germline
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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000767814.5
First in ClinVar: May 28, 2018 Last updated: Feb 07, 2023 |
Comment:
This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 77 of the TNNT2 protein (p.Pro77Leu). … (more)
This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 77 of the TNNT2 protein (p.Pro77Leu). This variant is present in population databases (rs144900708, gnomAD 0.02%). This missense change has been observed in individual(s) with TNNT2-related conditions (PMID: 11560853, 20530761). This variant is also known as p.Pro87Leu. ClinVar contains an entry for this variant (Variation ID: 43619). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt TNNT2 protein function. Experimental studies have shown that this missense change does not substantially affect TNNT2 function (PMID: 33025817). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)
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Uncertain significance
(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: SCV004181542.1
First in ClinVar: Dec 24, 2023 Last updated: Dec 24, 2023 |
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Uncertain significance
(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: SCV004181543.1
First in ClinVar: Dec 24, 2023 Last updated: Dec 24, 2023 |
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Uncertain significance
(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: SCV004181544.1
First in ClinVar: Dec 24, 2023 Last updated: Dec 24, 2023 |
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Uncertain significance
(Mar 15, 2023)
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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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Color Diagnostics, LLC DBA Color Health
Accession: SCV001351204.3
First in ClinVar: Jun 22, 2020 Last updated: Feb 14, 2024 |
Comment:
This missense variant replaces proline with leucine at codon 77 of the TNNT2 protein. Computational prediction suggests that this variant may have a deleterious impact … (more)
This missense variant replaces proline with leucine at codon 77 of the TNNT2 protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with hypertrophic cardiomyopathy and sudden cardiac death (PMID: 11560853) and in an individual affected with left ventricular noncompaction cardiomyopathy (PMID: 20530761). This variant has been identified in 10/251110 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. (less)
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Uncertain Significance
(Feb 05, 2024)
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criteria provided, single submitter
Method: clinical testing
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Cardiomyopathy
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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All of Us Research Program, National Institutes of Health
Accession: SCV004821981.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024
Comment:
This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of … (more)
This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of variant classification. Additional details can be found in publication PMID: 35346344, PMCID: PMC8962531 (less)
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Comment:
This missense variant replaces proline with leucine at codon 77 of the TNNT2 protein. Computational prediction suggests that this variant may have a deleterious impact … (more)
This missense variant replaces proline with leucine at codon 77 of the TNNT2 protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with hypertrophic cardiomyopathy and sudden cardiac death (PMID: 11560853) and in an individual affected with left ventricular noncompaction cardiomyopathy (PMID: 20530761). This variant has been identified in 10/251110 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. (less)
Number of individuals with the variant: 7
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Uncertain significance
(Dec 07, 2021)
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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: SCV004968976.1
First in ClinVar: May 01, 2024 Last updated: May 01, 2024 |
Comment:
The c.230C>T (p.P77L) alteration is located in exon 8 (coding exon 7) of the TNNT2 gene. This alteration results from a C to T substitution … (more)
The c.230C>T (p.P77L) alteration is located in exon 8 (coding exon 7) of the TNNT2 gene. This alteration results from a C to T substitution at nucleotide position 230, causing the proline (P) at amino acid position 77 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. (less)
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Uncertain significance
(Jun 01, 2014)
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no assertion criteria provided
Method: research
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Cardiomyopathy, hypertrophic
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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CSER _CC_NCGL, University of Washington
Study: ESP 6500 variant annotation
Accession: SCV000190648.1 First in ClinVar: Dec 06, 2014 Last updated: Dec 06, 2014
Comment:
Variants classified for the Actionable exomic incidental findings in 6503 participants: challenges of variant classification manuscript
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Uncertain significance
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Clinical Genetics, Academic Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001920415.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021 |
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Uncertain significance
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001966473.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021 |
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Uncertain significance
(Jul 26, 2024)
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no assertion criteria provided
Method: clinical testing
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TNNT2-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV005346059.1
First in ClinVar: Oct 08, 2024 Last updated: Oct 08, 2024 |
Comment:
The TNNT2 c.230C>T variant is predicted to result in the amino acid substitution p.Pro77Leu. This variant has been reported in an individual diagnosed with hypertrophic … (more)
The TNNT2 c.230C>T variant is predicted to result in the amino acid substitution p.Pro77Leu. This variant has been reported in an individual diagnosed with hypertrophic cardiomyopathy after sudden cardiac death (Varnava et al. 2001. PubMed ID: 11560853). This variant, also described as p.Pro87Leu, has also been reported in two members of a family with left ventricular noncompaction cardiomyopathy (Hoedemaekers et al. 2010. PubMed ID: 20530761). An in vitro reporter assay did not demonstrate a significant difference between this variant and wildtype (Figure 4G, Pettinato et al. 2020. PubMed ID: 33025817). This variant is reported in 0.017% of alleles in individuals of Latino descent in gnomAD, and has been consistently interpreted as uncertain by several laboratories in the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/43619/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. (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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Development of a Cardiac Sarcomere Functional Genomics Platform to Enable Scalable Interrogation of Human TNNT2 Variants. | Pettinato AM | Circulation | 2020 | PMID: 33025817 |
The importance of genetic counseling, DNA diagnostics, and cardiologic family screening in left ventricular noncompaction cardiomyopathy. | Hoedemaekers YM | Circulation. Cardiovascular genetics | 2010 | PMID: 20530761 |
Hypertrophic cardiomyopathy: histopathological features of sudden death in cardiac troponin T disease. | Varnava AM | Circulation | 2001 | PMID: 11560853 |
Text-mined citations for rs144900708 ...
HelpRecord last updated Oct 13, 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.