NM_000363.5(TNNI3):c.61C>T (p.Arg21Cys) AND Cardiovascular phenotype

This record was updated by the submitter. Please see the current version.

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Mar 1, 2021
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV002354158.1

Allele description

NM_000363.5(TNNI3):c.61C>T (p.Arg21Cys)

Gene:

TNNI3:troponin I3, cardiac type [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

19q13.42

Genomic location:

Preferred name:

NM_000363.5(TNNI3):c.61C>T (p.Arg21Cys)

HGVS:

NC_000019.10:g.55157097G>A
NG_007866.2:g.5636C>T
NG_032759.1:g.14626C>T
NM_000363.5:c.61C>TMANE SELECT
NP_000354.4:p.Arg21Cys
LRG_432t1:c.61C>T
LRG_432:g.5636C>T
LRG_432p1:p.Arg21Cys
NC_000019.9:g.55668465G>A
NM_000363.4:c.61C>T

Protein change:

R21C; ARG21CYS

Links:

OMIM: 191044.0016; dbSNP: rs267607128

NCBI 1000 Genomes Browser:

rs267607128

Molecular consequence:

NM_000363.5:c.61C>T - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Cardiovascular phenotype
Identifiers:: MedGen: CN230736

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002655053	Ambry Genetics	criteria provided, single submitter (Ambry General Variant Classification Scheme_2022)	Pathogenic (Mar 1, 2021)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 16005017, 22086914, 24111713, 24973218, 25961037, 26391394, 32885985 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002655053

Ambry Genetics

criteria provided, single submitter

(Ambry General Variant Classification Scheme_2022)

Pathogenic
(Mar 1, 2021)

germline

clinical testing

PubMed (7)
[See all records that cite these PMIDs]

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	1	not provided	not provided	1	not provided	clinical testing

Citations

PubMed

A mutation in the N-terminus of troponin I that is associated with hypertrophic cardiomyopathy affects the Ca(2+)-sensitivity, phosphorylation kinetics and proteolytic susceptibility of troponin.

Gomes AV, Harada K, Potter JD.

J Mol Cell Cardiol. 2005 Nov;39(5):754-65. Epub 2005 Jul 6.

PubMed [citation]

PMID:: 16005017

Generation and functional characterization of knock-in mice harboring the cardiac troponin I-R21C mutation associated with hypertrophic cardiomyopathy.

Wang Y, Pinto JR, Solis RS, Dweck D, Liang J, Diaz-Perez Z, Ge Y, Walker JW, Potter JD.

J Biol Chem. 2012 Jan 13;287(3):2156-67. doi: 10.1074/jbc.M111.294306. Epub 2011 Nov 15.

PubMed [citation]

PMID:: 22086914
PMCID:: PMC3265894

See all PubMed Citations (7)

Details of each submission

From Ambry Genetics, SCV002655053.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (7)

Description

The p.R21C variant (also known as c.61C>T), located in coding exon 3 of the TNNI3 gene, results from a C to T substitution at nucleotide position 61. The arginine at codon 21 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant has been detected in hypertrophic cardiomyopathy (HCM) cohorts (Berge KE et al. Clin Genet, 2014 Oct;86:355-60; Fahed AC et al. Circ Genom Precis Med, 2020 Oct;13:444-452), and it has been found to segregate with HCM and sudden cardiac death among multiple unrelated South Lebanese families (Fahed AC et al. Circ Genom Precis Med, 2020 Oct;13:444-452). Additionally, functional studies show that this alteration impacts protein function by altering phosphorylation and calcium sensitivity, which may lead to the development of a cardiomyopathy phenotype (Gomes AV et al. J Mol Cell Cardiol, 2005 Nov;39:754-65; Wang Y et al. J Biol Chem, 2012 Jan;287:2156-67; Dweck D et al. J Biol Chem, 2014 Aug;289:23097-111; Cheng Y et al. J Biol Chem, 2015 Nov;290:27749-66; Liang J et al. Biomed Res Int, 2015 Apr;2015:742536). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	1	not provided	not provided		1	not provided	not provided	not provided

Last Updated: Feb 14, 2024

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