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

This record was updated by the submitter. Please see the current version.

Germline classification:: Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:: Jan 22, 2024
Review status:: criteria provided, conflicting classifications

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:: RCV002513379.4

Allele description

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]

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
SCV003282082	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Jan 22, 2024)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 32870709, 15070570, 22940544, 28492532
SCV004821905	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain Significance (Oct 6, 2023)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 15070570, 22940544, 32746448, 32870709, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV003282082

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Jan 22, 2024)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

SCV004821905

All of Us Research Program, National Institutes of Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain Significance
(Oct 6, 2023)

germline

clinical testing

PubMed (5)
[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

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

See all PubMed Citations (6)

Details of each submission

From Invitae, SCV003282082.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 2 of the TNNI3 protein (p.Ala2Val). This variant is present in population databases (rs397516359, gnomAD 0.03%). This missense change has been observed in individuals with autosomal recessive dilated cardiomyopathy (PMID: 32870709; Invitae). ClinVar contains an entry for this variant (Variation ID: 43397). 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 disruptive. Experimental studies have shown that this missense change affects TNNI3 function (PMID: 15070570, 22940544). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

#	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, SCV004821905.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	2	not provided	not provided	clinical 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.

#	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: May 7, 2024

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