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

Clinical significance:Pathogenic (Last evaluated: Jan 31, 2019)

Review status:2 stars out of maximum of 4 stars

criteria provided, multiple submitters, no conflicts

Based on:
2 submissions [Details]
Record status:
current
Accession:
RCV000557688.2

Allele description [Variation Report for NM_000363.5(TNNI3):c.433C>G (p.Arg145Gly)]

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

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.433C>G (p.Arg145Gly)
HGVS:
  • NC_000019.10:g.55154146G>C
  • NG_007866.2:g.8587C>G
  • NG_011829.2:g.93C>G
  • NM_000363.5:c.433C>GMANE SELECT
  • NP_000354.4:p.Arg145Gly
  • LRG_432t1:c.433C>G
  • LRG_432:g.8587C>G
  • LRG_679:g.93C>G
  • NC_000019.9:g.55665514G>C
  • NM_000363.4:c.433C>G
  • P19429:p.Arg145Gly
  • c.433C>G
Protein change:
R145G; ARG145GLY
Links:
UniProtKB: P19429#VAR_007603; OMIM: 191044.0001; dbSNP: rs104894724
NCBI 1000 Genomes Browser:
rs104894724
Molecular consequence:
  • NM_000363.5:c.433C>G - missense variant - [Sequence Ontology: SO:0001583]
Observations:
1

Condition(s)

Name:
Hypertrophic cardiomyopathy
Identifiers:
MONDO: MONDO:0005045; MeSH: D002312; MedGen: C0007194; OMIM: PS192600; Human Phenotype Ontology: HP:0001639

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000059945Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicinecriteria provided, single submitter
Pathogenic
(Jan 31, 2019)
germlineclinical testing

PubMed (16)
[See all records that cite these PMIDs]

SCV000623781Invitaecriteria provided, single submitter
Pathogenic
(May 9, 2017)
germlineclinical testing

PubMed (1)
[See all records that cite this PMID]

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknown11not providednot providednot providedclinical testing

Citations

PubMed

Long-term outcome of 4 Korean families with hypertrophic cardiomyopathy caused by 4 different mutations.

Choi JO, Yu CW, Chun Nah J, Rang Park J, Lee BS, Jeong Choi Y, Cho BR, Lee SC, Woo Park S, Kimura A, Euy Park J.

Clin Cardiol. 2010 Jul;33(7):430-8. doi: 10.1002/clc.20795.

PubMed [citation]
PMID:
20641121
PMCID:
PMC6653452

Mutations in the cardiac troponin I gene associated with hypertrophic cardiomyopathy.

Kimura A, Harada H, Park JE, Nishi H, Satoh M, Takahashi M, Hiroi S, Sasaoka T, Ohbuchi N, Nakamura T, Koyanagi T, Hwang TH, Choo JA, Chung KS, Hasegawa A, Nagai R, Okazaki O, Nakamura H, Matsuzaki M, Sakamoto T, Toshima H, Koga Y, et al.

Nat Genet. 1997 Aug;16(4):379-82.

PubMed [citation]
PMID:
9241277
See all PubMed Citations (17)

Details of each submission

From Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine, SCV000059945.6

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testing PubMed (16)

Description

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 1997, Choi 2010, LMM data). This variant was absent from large population studies. In vitro functional studies provide some evidence that the p.Arg145Gly variant may impact protein function (Elliott 2000, Deng 2001, Kruger 2005, Robinson 2007). This variant was predicted 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). Additionally, two other disease-causing variants have been reported in this codon (p.Arg145Trp, p.Arg145Gln), further suppporting that changes in this codon are not tolerated. In summary, this variant meets criteria to be classified as pathogenic for HCM in an autosomal dominant manner based upon segregation studies, absence from controls, and functional evidence. ACMG/AMP Criteria applied: PP1_Strong; PM2; PM5; PS3_Moderate; PP3; PS4_Supporting.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot provided1not provided1not provided

From Invitae, SCV000623781.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)

Description

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 moderate physicochemical difference between arginine and glycine. This variant is present in the population databases (rs104894724, ExAC). This variant has been reported in several individuals with hypertrophic cardiomyopathy (HCM) and has been shown to segregate with disease in an affected family (PMID: 9241277, 20641121). ClinVar contains an entry for this variant (Variation ID: 12419). Experimental studies using several cellular, animal and human models have shown that this variant causes deleterious effects on several aspects of TNNI3 protein function including crossbridge and force kinetics and calcium sensitivity (PMID: 15718266, 11724573, 26391394, 22500102, 19289050, 11735257, 10806205). A different missense substitution at this codon (p.Arg145Trp) has been determined to be pathogenic (PMID: 21533915, 23283745, 27532257, 16531415, 18423659, 19289050, 19651143, 27557662 ). This suggests that the arginine residue is critical for TNNI3 protein function and that other missense substitutions at this position may also be pathogenic For these reasons, this variant has been classified as Pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Sep 26, 2021

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