NM_000363.5(TNNI3):c.298C>T (p.Leu100Phe) AND Hypertrophic cardiomyopathy

Germline classification:: Uncertain significance (4 submissions)
Last evaluated:: Sep 4, 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:: RCV000498021.7

Allele description [Variation Report for NM_000363.5(TNNI3):c.298C>T (p.Leu100Phe)]

NM_000363.5(TNNI3):c.298C>T (p.Leu100Phe)

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.298C>T (p.Leu100Phe)

HGVS:

NC_000019.10:g.55154815G>A
NG_007866.2:g.7918C>T
NM_000363.5:c.298C>TMANE SELECT
NP_000354.4:p.Leu100Phe
LRG_432t1:c.298C>T
LRG_432:g.7918C>T
NC_000019.9:g.55666183G>A
NM_000363.4:c.298C>T

Protein change:

L100F

Links:

dbSNP: rs773216333

NCBI 1000 Genomes Browser:

rs773216333

Molecular consequence:

NM_000363.5:c.298C>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
SCV000579542	Center for Human Genetics, University of Leuven	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Feb 9, 2017)	germline	clinical testing
SCV001430865	Agnes Ginges Centre for Molecular Cardiology, Centenary Institute	no assertion criteria provided	Uncertain significance (Mar 31, 2020)	germline	research	PubMed (1) [See all records that cite this PMID]
SCV003444320	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (May 22, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 29255176, 28492532
SCV004819081	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain Significance (Sep 4, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	research
not provided	germline	unknown	2	not provided	not provided	108544	not provided	clinical testing
Caucasian	germline	yes	1	1	not provided	not provided	yes	clinical testing

Citations

PubMed

Repeat genetic testing with targeted capture sequencing in primary arrhythmia syndrome and cardiomyopathy.

Robyns T, Kuiperi C, Breckpot J, Devriendt K, Souche E, Van Cleemput J, Willems R, Nuyens D, Matthijs G, Corveleyn A.

Eur J Hum Genet. 2017 Dec;25(12):1313-1323. doi: 10.1038/s41431-017-0004-3. Epub 2017 Oct 10.

PubMed [citation]

PMID:: 29255176
PMCID:: PMC5865127

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

See all PubMed Citations (3)

Details of each submission

From Center for Human Genetics, University of Leuven, SCV000579542.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	Caucasian	1	not provided	yes	clinical testing	not provided

Description

ACMG score unknown significance

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

From Agnes Ginges Centre for Molecular Cardiology, Centenary Institute, SCV001430865.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	research	PubMed (1)

Description

This variant has been identified as part of our research program. Refer to the 'condition' field for the phenotype of the proband identified with this variant. For further information please feel free to contact us.

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

From Labcorp Genetics (formerly Invitae), Labcorp, SCV003444320.2

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

Description

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. 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. ClinVar contains an entry for this variant (Variation ID: 427955). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 29255176). This variant is present in population databases (rs773216333, gnomAD 0.003%). This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 100 of the TNNI3 protein (p.Leu100Phe).

#	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, SCV004819081.1

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

Description

This missense variant replaces leucine with phenylalanine at codon 100 of the TNNI3 protein. Computational prediction tool suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >=0.7, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 3/249422 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 29, 2024

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