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

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Dec 22, 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:: RCV000628944.10

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]

Observations:

Condition(s)

Name:: Hypertrophic cardiomyopathy
Synonyms:: HYPERTROPHIC MYOCARDIOPATHY
Identifiers:: MONDO: MONDO:0005045; MeSH: D002312; MedGen: C0007194; Human Phenotype Ontology: HP:0001639

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000749852	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Dec 22, 2023)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 26936621, 27532257, 30731207, 34540771, 15774859, 17010989, 17872964, 28492532
SCV004819060	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain Significance (May 16, 2023)	germline	clinical testing	PubMed (9) [See all records that cite these PMIDs] 15774859, 17010989, 17872964, 23690394, 26936621, 27532257, 30731207, 34540771, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000749852

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Dec 22, 2023)

germline

clinical testing

PubMed (8)
[See all records that cite these PMIDs]

SCV004819060

All of Us Research Program, National Institutes of Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain Significance
(May 16, 2023)

germline

clinical testing

PubMed (9)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	2	not provided	not provided	108544	not provided	clinical testing

Citations

PubMed

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. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Functional effects of rho-kinase-dependent phosphorylation of specific sites on cardiac troponin.

Vahebi S, Kobayashi T, Warren CM, de Tombe PP, Solaro RJ.

Circ Res. 2005 Apr 15;96(7):740-7. Epub 2005 Mar 17.

PubMed [citation]

PMID:: 15774859

See all PubMed Citations (10)

Details of each submission

From Invitae, SCV000749852.7

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (8)

Description

This sequence change replaces threonine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 143 of the TNNI3 protein (p.Thr143Asn). This variant is present in population databases (rs397516348, gnomAD 0.01%). This missense change has been observed in individual(s) with clinical features of TNNI3-related conditions (PMID: 26936621, 27532257, 30731207, 34540771; Invitae). ClinVar contains an entry for this variant (Variation ID: 43382). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant¬†is likely to be tolerated. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on TNNI3 function (PMID: 15774859, 17010989, 17872964). 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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From All of Us Research Program, National Institutes of Health, SCV004819060.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	2	not provided	not provided	clinical testing	PubMed (9)

Description

This missense variant replaces threonine with asparagine at codon 143 of the TNNI3 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Experimental studies have suggested that this variant may abolish the phosphorylation site and may therefore have deleterious impact on the protein function (PMID: 15774859, 17010989, 17872964). However, clinical significance of these observations is unclear. This variant has been reported in individuals affected with or referred for testing for hypertrophic cardiomyopathy (PMID: 23690394, 26936621, 27532257, 30731207). Three of these individuals also carried pathogenic variants in the MYBPC3 and TPM1 gene (PMID: 26936621). It has also been reported in an individual affected with left ventricular noncompaction cardiomyopathy (PMID: 34540771). This variant has been identified in 9/248930 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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	108544	not provided	not provided		2	not provided	not provided	not provided

Last Updated: Sep 16, 2024

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