NM_000363.5(TNNI3):c.374T>C (p.Ile125Thr) AND Hypertrophic cardiomyopathy

Clinical significance:Uncertain significance (Last evaluated: Nov 24, 2015)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
1 submission [Details]
Record status:

Allele description [Variation Report for NM_000363.5(TNNI3):c.374T>C (p.Ile125Thr)]

NM_000363.5(TNNI3):c.374T>C (p.Ile125Thr)

TNNI3:troponin I3, cardiac type [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
Genomic location:
Preferred name:
NM_000363.5(TNNI3):c.374T>C (p.Ile125Thr)
  • NC_000019.10:g.55154205A>G
  • NG_007866.2:g.8528T>C
  • NG_011829.2:g.34T>C
  • NM_000363.5:c.374T>CMANE SELECT
  • NP_000354.4:p.Ile125Thr
  • LRG_432t1:c.374T>C
  • LRG_432:g.8528T>C
  • LRG_679:g.34T>C
  • NC_000019.9:g.55665573A>G
  • NM_000363.4:c.374T>C
Protein change:
dbSNP: rs878853956
NCBI 1000 Genomes Browser:
Molecular consequence:
  • NM_000363.5:c.374T>C - missense variant - [Sequence Ontology: SO:0001583]


Hypertrophic cardiomyopathy
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)
SCV000284658Invitaecriteria provided, single submitter
Uncertain significance
(Nov 24, 2015)
germlineclinical testing

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

Summary from all submissions

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



Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240-242.

PubMed [citation]

Details of each submission

From Invitae, SCV000284658.2

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


This sequence change replaces isoleucine with threonine at codon 125 of the TNNI3 protein (p.Ile125Thr). The isoleucine residue is highly conserved and there is a moderate physicochemical difference between isoleucine and threonine. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature. A computational algorithm designed to assess the pathogenicity of missense variants in TNNI3 with regard to hypertrophic cardiomyopathy predicted this sequence change to be pathogenic. The algorithm has a sensitivity of 94% and a specificity of 89% (PMID: 21310275). This missense change is located within exon 8 of the TNNI3 protein and a high percentage of previously reported TNNI3 missense mutations have been found within either exon 7 or exon 8 (PMID: 15607392). These observations suggest that a novel missense substitution within this exon may affect protein function, but experiments have not been done to test this possibility. In summary, this is a novel missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance.

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

Last Updated: Oct 7, 2021

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