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NM_000363.5(TNNI3):c.5C>T (p.Ala2Val) AND Cardiomyopathy

Germline classification:
Uncertain significance (2 submissions)
Last evaluated:
Jun 8, 2023
Review status:
2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts
Somatic classification
of clinical impact:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Somatic classification
of oncogenicity:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Record status:
current
Accession:
RCV000769534.7

Allele description [Variation Report for NM_000363.5(TNNI3):c.5C>T (p.Ala2Val)]

NM_000363.5(TNNI3):c.5C>T (p.Ala2Val)

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.5C>T (p.Ala2Val)
HGVS:
  • NC_000019.10:g.55157585G>A
  • NG_007866.2:g.5148C>T
  • NG_032759.1:g.14138C>T
  • NM_000363.5:c.5C>TMANE SELECT
  • NP_000354.4:p.Ala2Val
  • LRG_432t1:c.5C>T
  • LRG_432:g.5148C>T
  • NC_000019.9:g.55668953G>A
  • NM_000363.4:c.5C>T
  • P19429:p.Ala2Val
  • c.5C>T
Protein change:
A2V
Links:
LOVD 3: TNNI3_000039; UniProtKB: P19429#VAR_043989; OMIM: 191044.0009; dbSNP: rs397516359
NCBI 1000 Genomes Browser:
rs397516359
Molecular consequence:
  • NM_000363.5:c.5C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Cardiomyopathy (CMYO)
Synonyms:
Cardiomyopathies
Identifiers:
MONDO: MONDO:0004994; MedGen: C0878544; Human Phenotype Ontology: HP:0001638

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV000900929CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario - Canadian Open Genetics Repository
criteria provided, single submitter

(ACMG Guidelines, 2015)		Uncertain significance
(Dec 20, 2019) 		germlineclinical testing

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

SCV001360401Color Diagnostics, LLC DBA Color Health
criteria provided, single submitter

(ACMG Guidelines, 2015)		Uncertain significance
(Jun 8, 2023) 		germlineclinical testing

PubMed (5)
[See all records that cite these PMIDs]

Help

Summary from all submissions

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

Citations

PubMed

Novel mutation in cardiac troponin I in recessive idiopathic dilated cardiomyopathy.

Murphy RT, Mogensen J, Shaw A, Kubo T, Hughes S, McKenna WJ.

Lancet. 2004 Jan 31;363(9406):371-2.

PubMed [citation]
PMID:
15070570

New insights into the functional significance of the acidic region of the unique N-terminal extension of cardiac troponin I.

Henze M, Patrick SE, Hinken A, Scruggs SB, Goldspink P, de Tombe PP, Kobayashi M, Ping P, Kobayashi T, Solaro RJ.

Biochim Biophys Acta. 2013 Apr;1833(4):823-32. doi: 10.1016/j.bbamcr.2012.08.012. Epub 2012 Aug 25.

PubMed [citation]
PMID:
22940544
PMCID:
PMC3548050
See all PubMed Citations (5)

Details of each submission

From CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario - Canadian Open Genetics Repository, SCV000900929.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Color Diagnostics, LLC DBA Color Health, SCV001360401.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (5)

Description

This missense variant replaces alanine with valine at codon 2 of the TNNI3 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Functional studies have shown that this variant disrupts the interaction between troponin I and troponin T (PMID: 15070570), and affects myofilament function (PMID: 22940544). This variant has been reported in homozygous state in two siblings affected with dilated cardiomyopathy (PMID: 15070570); their parents and another sibling were all healthy heterozygous carriers. This variant has also been reported in homozygous state in an individual affected with childhood-onset dilated cardiomyopathy (PMID: 32870709) and in unspecified zygosity in another individual affected with childhood-onset dilated cardiomyopathy (PMID: 32746448). This variant has also been identified in 8/248866 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

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

Last Updated: May 7, 2024