NM_000363.5(TNNI3):c.533A>G (p.Lys178Arg) AND Hypertrophic cardiomyopathy

Clinical significance:Uncertain significance (Last evaluated: Apr 9, 2019)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
1 submission [Details]
Record status:
current
Accession:
RCV001044658.2

Allele description [Variation Report for NM_000363.5(TNNI3):c.533A>G (p.Lys178Arg)]

NM_000363.5(TNNI3):c.533A>G (p.Lys178Arg)

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.533A>G (p.Lys178Arg)
HGVS:
  • NC_000019.10:g.55154046T>C
  • NG_007866.2:g.8687A>G
  • NG_011829.2:g.193A>G
  • NM_000363.5:c.533A>GMANE SELECT
  • NP_000354.4:p.Lys178Arg
  • LRG_432t1:c.533A>G
  • LRG_432:g.8687A>G
  • LRG_679:g.193A>G
  • NC_000019.9:g.55665414T>C
  • NM_000363.4:c.533A>G
Protein change:
K178R
Molecular consequence:
  • NM_000363.5:c.533A>G - 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
SCV001208464Invitaecriteria provided, single submitter
Uncertain significance
(Apr 9, 2019)
germlineclinical testing

PubMed (4)
[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

Idiopathic restrictive cardiomyopathy is part of the clinical expression of cardiac troponin I mutations.

Mogensen J, Kubo T, Duque M, Uribe W, Shaw A, Murphy R, Gimeno JR, Elliott P, McKenna WJ.

J Clin Invest. 2003 Jan;111(2):209-16. Erratum in: J Clin Invest. 2003 Mar;111(6):925.

PubMed [citation]
PMID:
12531876
PMCID:
PMC151864

Reassessment of Mendelian gene pathogenicity using 7,855 cardiomyopathy cases and 60,706 reference samples.

Walsh R, Thomson KL, Ware JS, Funke BH, Woodley J, McGuire KJ, Mazzarotto F, Blair E, Seller A, Taylor JC, Minikel EV, Exome Aggregation Consortium, MacArthur DG, Farrall M, Cook SA, Watkins H.

Genet Med. 2017 Feb;19(2):192-203. doi: 10.1038/gim.2016.90. Epub 2016 Aug 17.

PubMed [citation]
PMID:
27532257
PMCID:
PMC5116235
See all PubMed Citations (4)

Details of each submission

From Invitae, SCV001208464.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (4)

Description

This sequence change replaces lysine with arginine at codon 178 of the TNNI3 protein (p.Lys178Arg). The lysine residue is highly conserved and there is a small physicochemical difference between lysine and arginine. 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.Lys178 amino acid residue in TNNI3. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12531876, 27532257, 29907873). 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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