NM_000363.5(TNNI3):c.434G>T (p.Arg145Leu) AND Hypertrophic cardiomyopathy

Clinical significance:Uncertain significance (Last evaluated: Mar 18, 2020)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
1 submission [Details]
Record status:
current
Accession:
RCV001338929.1

Allele description [Variation Report for NM_000363.5(TNNI3):c.434G>T (p.Arg145Leu)]

NM_000363.5(TNNI3):c.434G>T (p.Arg145Leu)

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.434G>T (p.Arg145Leu)
HGVS:
  • NC_000019.10:g.55154145C>A
  • NG_007866.2:g.8588G>T
  • NG_011829.2:g.94G>T
  • NM_000363.5:c.434G>TMANE SELECT
  • NP_000354.4:p.Arg145Leu
  • LRG_432:g.8588G>T
  • LRG_679:g.94G>T
  • NC_000019.9:g.55665513C>A
Protein change:
R145L
Molecular consequence:
  • NM_000363.5:c.434G>T - missense variant - [Sequence Ontology: SO:0001583]

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
SCV001532634Invitaecriteria provided, single submitter
Uncertain significance
(Mar 18, 2020)
germlineclinical testing

PubMed (6)
[See all records that cite these PMIDs]

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

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

Frequency and clinical expression of cardiac troponin I mutations in 748 consecutive families with hypertrophic cardiomyopathy.

Mogensen J, Murphy RT, Kubo T, Bahl A, Moon JC, Klausen IC, Elliott PM, McKenna WJ.

J Am Coll Cardiol. 2004 Dec 21;44(12):2315-25.

PubMed [citation]
PMID:
15607392
See all PubMed Citations (6)

Details of each submission

From Invitae, SCV001532634.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (6)

Description

This sequence change replaces arginine with leucine at codon 145 of the TNNI3 protein (p.Arg145Leu). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and leucine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with TNNI3-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant disrupts the p.Arg145 amino acid residue in TNNI3. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9241277, 15607392, 23283745, 24111713, 25132132). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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.

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

Last Updated: Oct 7, 2021

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