NM_000363.5(TNNI3):c.428C>A (p.Thr143Asn) AND Hypertrophic cardiomyopathy

Clinical significance:Uncertain significance (Last evaluated: Apr 17, 2019)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
1 submission [Details]
Record status:
current
Accession:
RCV000628944.4

Allele description [Variation Report for NM_000363.5(TNNI3):c.428C>A (p.Thr143Asn)]

NM_000363.5(TNNI3):c.428C>A (p.Thr143Asn)

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.428C>A (p.Thr143Asn)
Other names:
p.T143N:ACC>AAC
HGVS:
  • NC_000019.10:g.55154151G>T
  • NG_007866.2:g.8582C>A
  • NG_011829.2:g.88C>A
  • NM_000363.5:c.428C>AMANE SELECT
  • NP_000354.4:p.Thr143Asn
  • LRG_432t1:c.428C>A
  • LRG_432:g.8582C>A
  • LRG_679:g.88C>A
  • NC_000019.9:g.55665519G>T
  • NM_000363.4:c.428C>A
  • c.428C>A
Protein change:
T143N
Links:
dbSNP: rs397516348
NCBI 1000 Genomes Browser:
rs397516348
Molecular consequence:
  • NM_000363.5:c.428C>A - 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
SCV000749852Invitaecriteria provided, single submitter
Uncertain significance
(Apr 17, 2019)
germlineclinical testing

PubMed (8)
[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

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

Comparison of echocardiographic and cardiac magnetic resonance imaging in hypertrophic cardiomyopathy sarcomere mutation carriers without left ventricular hypertrophy.

Valente AM, Lakdawala NK, Powell AJ, Evans SP, Cirino AL, Orav EJ, MacRae CA, Colan SD, Ho CY.

Circ Cardiovasc Genet. 2013 Jun;6(3):230-7. doi: 10.1161/CIRCGENETICS.113.000037. Epub 2013 May 20.

PubMed [citation]
PMID:
23690394
PMCID:
PMC3974911
See all PubMed Citations (8)

Details of each submission

From Invitae, SCV000749852.4

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (8)

Description

This sequence change replaces threonine with asparagine at codon 143 of the TNNI3 protein (p.Thr143Asn). The threonine residue is highly conserved and there is a small physicochemical difference between threonine and asparagine. This variant is present in population databases (rs397516348, ExAC 0.006%). This variant has been reported in an individual affected with cardiomyopathy and in individuals referred for testing for hypertrophic cardiomyopathy (PMID: 27532257, 23690394). In addition, this variant has been reported in a parent and child with hypertrophic cardiomyopath. In this family, the parent carried a second missense variant in the TPM1 gene, and the child carried both a pathogenic variant in MYBPC3 and the variant in TPM1 (PMID: 26936621). ClinVar contains an entry for this variant (Variation ID: 43382). Experimental studies using an animal model have suggested that the threonine at position 143, corresponding to threonine at position 144 in mice, may be involved in phosphorylation and myofilament response to calcium regulation (PMID: 17010989, 17872964, 15774859). However, the clinical significance of these findings is unclear. An algorithm developed specifically for the TNNI3 gene suggests that this missense change is likely to be deleterious (PMID: 21310275). However, this prediction has not been confirmed by published functional studies and its clinical significance is uncertain. 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 6, 2021

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