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NM_000363.5(TNNI3):c.433C>G (p.Arg145Gly)

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Interpretation:
Pathogenic​

Review status:
criteria provided, multiple submitters, no conflicts
Submissions:
5 (Most recent: Sep 24, 2021)
Last evaluated:
Mar 26, 2021
Accession:
VCV000012419.7
Variation ID:
12419
Description:
single nucleotide variant
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NM_000363.5(TNNI3):c.433C>G (p.Arg145Gly)

Allele ID
27458
Variant type
single nucleotide variant
Variant length
1 bp
Cytogenetic location
19q13.42
Genomic location
19: 55154146 (GRCh38) GRCh38 UCSC
19: 55665514 (GRCh37) GRCh37 UCSC
HGVS
Nucleotide Protein Molecular
consequence
P19429:p.Arg145Gly
NC_000019.10:g.55154146G>C
NC_000019.9:g.55665514G>C
... more HGVS
Protein change
R145G
Other names
-
Canonical SPDI
NC_000019.10:55154145:G:C
Functional consequence
-
Global minor allele frequency (GMAF)
-

Allele frequency
-
Links
ClinGen: CA021660
UniProtKB: P19429#VAR_007603
OMIM: 191044.0001
dbSNP: rs104894724
VarSome
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Aggregate interpretations per condition

Interpreted condition Interpretation Number of submissions Review status Last evaluated Variation/condition record
Pathogenic 2 criteria provided, multiple submitters, no conflicts Jan 31, 2019 RCV000557688.2
Pathogenic 1 criteria provided, single submitter Dec 21, 2015 RCV000251781.1
Pathogenic 1 criteria provided, single submitter Mar 26, 2021 RCV000441050.2
Pathogenic 1 no assertion criteria provided Jul 18, 2008 RCV000013231.26
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Gene OMIM ClinGen Gene Dosage Sensitivity Curation Variation viewer Related variants
HI score Help TS score Help Within gene All
TNNI3 Little evidence for dosage pathogenicity No evidence available GRCh38
GRCh37
438 493

Submitted interpretations and evidence

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Interpretation
(Last evaluated)
Review status
(Assertion criteria)
Condition
(Inheritance)
Submitter Supporting information
Pathogenic
(May 09, 2017)
criteria provided, single submitter
Method: clinical testing
Hypertrophic cardiomyopathy
Allele origin: germline
Invitae
Accession: SCV000623781.1
Submitted: (Oct 05, 2017)
Evidence details
Comment:
This sequence change replaces arginine with glycine at codon 145 of the TNNI3 protein (p.Arg145Gly). The arginine residue is highly conserved and there is a … (more)
Pathogenic
(Jan 31, 2019)
criteria provided, single submitter
Method: clinical testing
Hypertrophic cardiomyopathy
(Autosomal dominant inheritance)
Allele origin: germline
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine
Accession: SCV000059945.6
Submitted: (Jun 03, 2020)
Evidence details
Publications
PubMed (15)
Comment:
The p.Arg145Gly variant in TNNI3 has been reported in 3 individuals with HCM and segregated with disease in 10 affected relatives from 2 families (Kimura … (more)
Pathogenic
(Dec 21, 2015)
criteria provided, single submitter
Method: clinical testing
Cardiovascular phenotype
Allele origin: germline
Ambry Genetics
Accession: SCV000320677.5
Submitted: (Nov 30, 2020)
Evidence details
Publications
PubMed (8)
Comment:
Thep.R145Gpathogenic mutation(also known as c.433C>G), located in codingexon7 of theTNNI3gene, results from a C to G substitution at nucleotide position 433. Thearginineatcodon145 is replaced byglycine, … (more)
Pathogenic
(Mar 26, 2021)
criteria provided, single submitter
Method: clinical testing
Not Provided
Allele origin: germline
GeneDx
Accession: SCV000517404.4
Submitted: (Sep 24, 2021)
Evidence details
Comment:
Not observed in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; … (more)
Pathogenic
(Jul 18, 2008)
no assertion criteria provided
Method: literature only
CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 7
Allele origin: germline
OMIM
Accession: SCV000033478.2
Submitted: (Dec 30, 2010)
Evidence details
Publications
PubMed (3)

Functional evidence

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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 this variant

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Title Author Journal Year Link
Targeted Next-Generation Sequencing Reveals Hot Spots and Doubly Heterozygous Mutations in Chinese Patients with Familial Cardiomyopathy. Zhao Y BioMed research international 2015 PMID: 26199943
Long-term outcome of 4 Korean families with hypertrophic cardiomyopathy caused by 4 different mutations. Choi JO Clinical cardiology 2010 PMID: 20641121
Expression of cTnI-R145G affects shortening properties of adult rat cardiomyocytes. Reis S Pflugers Archiv : European journal of physiology 2008 PMID: 18548271
Functional consequences of the human cardiac troponin I hypertrophic cardiomyopathy mutation R145G in transgenic mice. Wen Y The Journal of biological chemistry 2008 PMID: 18430738
Dilated and hypertrophic cardiomyopathy mutations in troponin and alpha-tropomyosin have opposing effects on the calcium affinity of cardiac thin filaments. Robinson P Circulation research 2007 PMID: 17932326
Increased Ca2+ affinity of cardiac thin filaments reconstituted with cardiomyopathy-related mutant cardiac troponin I. Kobayashi T The Journal of biological chemistry 2006 PMID: 16531415
The role of electrostatics in the interaction of the inhibitory region of troponin I with troponin C. Lindhout DA Biochemistry 2005 PMID: 16274223
Effects of the mutation R145G in human cardiac troponin I on the kinetics of the contraction-relaxation cycle in isolated cardiac myofibrils. Kruger M The Journal of physiology 2005 PMID: 15718266
Frequency and clinical expression of cardiac troponin I mutations in 748 consecutive families with hypertrophic cardiomyopathy. Mogensen J Journal of the American College of Cardiology 2004 PMID: 15607392
Calpain-1-dependent degradation of troponin I mutants found in familial hypertrophic cardiomyopathy. Barta J Molecular and cellular biochemistry 2003 PMID: 14575308
Idiopathic restrictive cardiomyopathy is part of the clinical expression of cardiac troponin I mutations. Mogensen J The Journal of clinical investigation 2003 PMID: 12531876
Effects of T142 phosphorylation and mutation R145G on the interaction of the inhibitory region of human cardiac troponin I with the C-domain of human cardiac troponin C. Lindhout DA Biochemistry 2002 PMID: 12044157
Two mutations in troponin I that cause hypertrophic cardiomyopathy have contrasting effects on cardiac muscle contractility. Burton D The Biochemical journal 2002 PMID: 11853553
Functional analysis of a troponin I (R145G) mutation associated with familial hypertrophic cardiomyopathy. Lang R The Journal of biological chemistry 2002 PMID: 11801593
Effects of phosphorylation and mutation R145G on human cardiac troponin I function. Deng Y Biochemistry 2001 PMID: 11724573
Transgenic modeling of a cardiac troponin I mutation linked to familial hypertrophic cardiomyopathy. James J Circulation research 2000 PMID: 11055985
Altered regulatory properties of human cardiac troponin I mutants that cause hypertrophic cardiomyopathy. Elliott K The Journal of biological chemistry 2000 PMID: 10806205
Effect of Arg145Gly mutation in human cardiac troponin I on the ATPase activity of cardiac myofibrils. Takahashi-Yanaga F Journal of biochemistry 2000 PMID: 10731705
Mutations in the cardiac troponin I gene associated with hypertrophic cardiomyopathy. Kimura A Nature genetics 1997 PMID: 9241277

Text-mined citations for rs104894724...

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These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Sep 26, 2021