ClinVar Genomic variation as it relates to human health
NM_001276345.2(TNNT2):c.566C>T (p.Ser189Phe)
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
-
NM_001276345.2(TNNT2):c.566C>T (p.Ser189Phe)
Variation ID: 177634 Accession: VCV000177634.25
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 1q32.1 1: 201363330 (GRCh38) [ NCBI UCSC ] 1: 201332458 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
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 Jan 31, 2015 May 1, 2024 Jul 24, 2023 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_001276345.2:c.566C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001263274.1:p.Ser189Phe missense NM_000364.4:c.566C>T NP_000355.2:p.Ser189Phe missense NM_001001430.3:c.536C>T NP_001001430.1:p.Ser179Phe missense NM_001001431.3:c.536C>T NP_001001431.1:p.Ser179Phe missense NM_001001432.3:c.521C>T NP_001001432.1:p.Ser174Phe missense NM_001276346.2:c.446C>T NP_001263275.1:p.Ser149Phe missense NM_001276347.2:c.536C>T NP_001263276.1:p.Ser179Phe missense NC_000001.11:g.201363330G>A NC_000001.10:g.201332458G>A NG_007556.1:g.19348C>T LRG_431:g.19348C>T LRG_431t1:c.566C>T LRG_431p1:p.Ser189Phe P45379:p.Ser189Phe - Protein change
- S179F, S189F, S149F, S174F
- Other names
- -
- Canonical SPDI
- NC_000001.11:201363329:G:A
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
-
-
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.
-
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
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 | ||
---|---|---|---|---|---|---|
HI score
Help
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. |
|||
TNNT2 | No evidence available | No evidence available |
GRCh38 GRCh37 |
954 | 972 |
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. |
---|---|---|---|---|
Likely pathogenic (1) |
criteria provided, single submitter
|
Jul 26, 2010 | RCV000154216.5 | |
Pathogenic (1) |
criteria provided, single submitter
|
Jul 24, 2023 | RCV000471745.12 | |
Likely pathogenic (1) |
criteria provided, single submitter
|
Apr 26, 2023 | RCV000617860.4 | |
Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Apr 11, 2023 | RCV001004907.5 | |
Likely pathogenic (1) |
criteria provided, single submitter
|
Apr 11, 2023 | RCV003453150.1 | |
Likely pathogenic (1) |
criteria provided, single submitter
|
Apr 11, 2023 | RCV003453149.1 |
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. |
|
---|---|---|---|---|---|
Likely pathogenic
(Jul 26, 2010)
|
criteria provided, single submitter
Method: clinical testing
|
Hypertrophic cardiomyopathy
Affected status: not provided
Allele origin:
germline
|
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000203870.5
First in ClinVar: Jan 31, 2015 Last updated: Aug 26, 2019 |
Comment:
The Ser179Phe variant in TNNT2 has been reported in one consanguineous family wi th HCM where it was present in 2 heterozygous individuals with mild … (more)
The Ser179Phe variant in TNNT2 has been reported in one consanguineous family wi th HCM where it was present in 2 heterozygous individuals with mild HCM and in 1 homozygous individual who died early due to a severe form of HCM (Ho 2000). Thi s variant has also been identified by our laboratory in 1 adult and 1 child with HCM, and was absent from large population studies. The Ser179Phe variant was pr edicted to be pathogenic using a computational tool clinically validated by our laboratory. This tool's pathogenic prediction is estimated to be correct 94% of the time (Jordan 2011), which strongly supports but does not prove that the Ser1 79Phe variant is pathogenic. In summary, this variant is likely to be pathogenic and causative for HCM, though evidence suggests a milder form when present in t he heterozygous state. (less)
Number of individuals with the variant: 7
|
|
Likely pathogenic
(Dec 03, 2018)
|
criteria provided, single submitter
Method: research
|
Hypertrophic cardiomyopathy 2
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
|
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard
Accession: SCV001164409.1
First in ClinVar: Mar 01, 2020 Last updated: Mar 01, 2020 |
Comment:
The heterozygous p.Ser179Phe variant in TNNT2 was identified by our study in one individual with familial hypertrophic cardiomyopathy. This variant was absent from large population … (more)
The heterozygous p.Ser179Phe variant in TNNT2 was identified by our study in one individual with familial hypertrophic cardiomyopathy. This variant was absent from large population studies. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. The p.Ser179Phe variant in TNNT2 has been reported in 6 individuals with familial hypertrophic cardiomyopathy, segregated with disease in 6 affected relatives from a cosanguineous, two-generation family. One individual died suddenly at 17 years of age and was homozygous for the variant and the other 5 individuals were heterozygous for the variant (PMID: 11034944). This variant has been reported pathogenic and likely pathogenic in ClinVar and two individuals with this variant in the heterozygous state and with familial hypertrophic cardiomyopathy were reported in ClinVar (Variation ID: 177634). In summary, although additional studies are required to fully establish its clinical significance, the p.Ser179Phe variant is likely pathogenic. ACMG/AMP Criteria applied: PM2, PP3, PP1_Strong (Richards 2015). (less)
|
|
Likely pathogenic
(Apr 11, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Cardiomyopathy, familial restrictive, 3
Affected status: no
Allele origin:
germline
|
Genome-Nilou Lab
Accession: SCV004181303.1
First in ClinVar: Dec 24, 2023 Last updated: Dec 24, 2023 |
|
|
Likely pathogenic
(Apr 11, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Dilated cardiomyopathy 1D
Affected status: no
Allele origin:
germline
|
Genome-Nilou Lab
Accession: SCV004181302.1
First in ClinVar: Dec 24, 2023 Last updated: Dec 24, 2023 |
|
|
Likely pathogenic
(Apr 11, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Hypertrophic cardiomyopathy 2
Affected status: no
Allele origin:
germline
|
Genome-Nilou Lab
Accession: SCV004181304.1
First in ClinVar: Dec 24, 2023 Last updated: Dec 24, 2023 |
|
|
Pathogenic
(Jul 24, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
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
|
Invitae
Accession: SCV000541923.10
First in ClinVar: Apr 17, 2017 Last updated: Feb 28, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, … (more)
For these reasons, this variant has been classified as Pathogenic. 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. ClinVar contains an entry for this variant (Variation ID: 177634). This missense change has been observed in individuals with clinical findings consistent with hypertrophic cardiomyopathy (HCM) , including a homozygous individual with severe HCM and HCM tested at a diagnostic laboratory (PMID: 11034944, 24033266, 27532257). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 179 of the TNNT2 protein (p.Ser179Phe). (less)
|
|
Likely pathogenic
(Apr 26, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Cardiovascular phenotype
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000736253.6
First in ClinVar: Apr 14, 2018 Last updated: May 01, 2024 |
Comment:
The p.S179F variant (also known as c.536C>T), located in coding exon 10 of the TNNT2 gene, results from a C to T substitution at nucleotide … (more)
The p.S179F variant (also known as c.536C>T), located in coding exon 10 of the TNNT2 gene, results from a C to T substitution at nucleotide position 536. The serine at codon 179 is replaced by phenylalanine, an amino acid with highly dissimilar properties. This alteration was first reported in a consanguineous family with a history of hypertrophic cardiomyopathy (HCM) and sudden death. Two heterozygous individuals presented with a mild form of HCM; the variant was present in the homozygous state in an individual with a severe phenotype (Ho CY et al., Circulation 2000 Oct; 102(16):1950-5). This variant has also been detected in individuals from additional HCM cohorts or cohorts submitted for HCM genetic testing (Walsh R et al. Genet. Med., 2017 Feb;19:192-203; Burstein DS et al. Pediatr Res. 2021 May;89(6):1470-1476). Functional studies suggest this variant may impact protein function through increased calcium sensitivity and force development; however, the physiological relevance of this finding has not been fully elucidated (Messer AE et al., Arch. Biochem. Biophys. 2016; doi: 10.1016/j.abb.2016.03.027; Harada K et al. J Biol Chem. 2004 Apr;279(15):14488-95). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of the available evidence, this alteration is likely to be pathogenic. (less)
|
|
Likely pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
Hypertrophic cardiomyopathy 2
Affected status: yes
Allele origin:
germline
|
Genomics England Pilot Project, Genomics England
Accession: SCV001760002.1
First in ClinVar: Jul 27, 2021 Last updated: Jul 27, 2021 |
|
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 |
---|---|---|---|---|
Suppression of lusitropy as a disease mechanism in cardiomyopathies. | Marston S | Frontiers in cardiovascular medicine | 2023 | PMID: 36698941 |
Genetic variant burden and adverse outcomes in pediatric cardiomyopathy. | Burstein DS | Pediatric research | 2021 | PMID: 32746448 |
Development of a Cardiac Sarcomere Functional Genomics Platform to Enable Scalable Interrogation of Human TNNT2 Variants. | Pettinato AM | Circulation | 2020 | PMID: 33025817 |
Reassessment of Mendelian gene pathogenicity using 7,855 cardiomyopathy cases and 60,706 reference samples. | Walsh R | Genetics in medicine : official journal of the American College of Medical Genetics | 2017 | PMID: 27532257 |
Targeted next-generation sequencing helps to decipher the genetic and phenotypic heterogeneity of hypertrophic cardiomyopathy. | Cecconi M | International journal of molecular medicine | 2016 | PMID: 27600940 |
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 |
A systematic approach to assessing the clinical significance of genetic variants. | Duzkale H | Clinical genetics | 2013 | PMID: 24033266 |
Familial hypertrophic cardiomyopathy mutations from different functional regions of troponin T result in different effects on the pH and Ca2+ sensitivity of cardiac muscle contraction. | Harada K | The Journal of biological chemistry | 2004 | PMID: 14722098 |
Prevalence and severity of "benign" mutations in the beta-myosin heavy chain, cardiac troponin T, and alpha-tropomyosin genes in hypertrophic cardiomyopathy. | Van Driest SL | Circulation | 2002 | PMID: 12473556 |
Homozygous mutation in cardiac troponin T: implications for hypertrophic cardiomyopathy. | Ho CY | Circulation | 2000 | PMID: 11034944 |
Text-mined citations for rs727504246 ...
HelpRecord last updated May 01, 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.