rs1060499912

Variant names:

• chr19-55154040-T-C
• rs1060499912
• NM_000363.5:c.539A>G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The NM_000363.5(TNNI3):​c.539A>G​(p.Asp180Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: TNNI3 NM_000363.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:8
• Conservation: PhyloP100: 2.56

Genes affected

TNNI3 (HGNC:11947): (troponin I3, cardiac type) Troponin I (TnI), along with troponin T (TnT) and troponin C (TnC), is one of 3 subunits that form the troponin complex of the thin filaments of striated muscle. TnI is the inhibitory subunit; blocking actin-myosin interactions and thereby mediating striated muscle relaxation. The TnI subfamily contains three genes: TnI-skeletal-fast-twitch, TnI-skeletal-slow-twitch, and TnI-cardiac. This gene encodes the TnI-cardiac protein and is exclusively expressed in cardiac muscle tissues. Mutations in this gene cause familial hypertrophic cardiomyopathy type 7 (CMH7) and familial restrictive cardiomyopathy (RCM). Troponin I is useful in making a diagnosis of heart failure, and of ischemic heart disease. An elevated level of troponin is also now used as indicator of acute myocardial injury in patients hospitalized with moderate/severe Coronavirus Disease 2019 (COVID-19). Such elevation has also been associated with higher risk of mortality in cardiovascular disease patients hospitalized due to COVID-19. [provided by RefSeq, Aug 2020]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM1: In a helix (size 25) in uniprot entity TNNI3_HUMAN there are 19 pathogenic changes around while only 0 benign (100%) in NM_000363.5
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNNI3	NM_000363.5	c.539A>G	p.Asp180Gly	missense_variant	Exon 7 of 8	ENST00000344887.10	NP_000354.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TNNI3	ENST00000344887.10	c.539A>G	p.Asp180Gly	missense_variant	Exon 7 of 8	1	NM_000363.5	ENSP00000341838.5

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:4

Jan 31, 2025

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Identified in patients with dilated cardiomyopathy referred for genetic testing at GeneDx and in published literature and also reported in a three month old infant with left ventricular non-compaction (PMID: 31737537, 30847666, 20215591, 20530761, 21483645, 23785128, 31112419, 21533915); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 23785128, 21533915, 20530761, 21483645, 31112419, 20215591, 31737537, 30847666) -

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Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

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Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

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Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

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not specified Uncertain:1

Aug 12, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Reported in 2 DCM and 1 LVNC probands, ClinVar: LP by GeneDx -

Cardiomyopathy Uncertain:1

Apr 19, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces aspartic acid with glycine at codon 180 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with dilated cardiomyopathy (PMID: 20215591, 21483645, 23785128, 25163546, 30847666, 31112419, 31737537). It has also been reported in an individual affected with left ventricular noncompaction (PMID: 20530761, 21533915, 31771441) and in an individual affected with noncompaction cardiomyopathy (PMID: 29447731). This variant has not been identified 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. -

Hypertrophic cardiomyopathy Uncertain:1

Dec 27, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 180 of the TNNI3 protein (p.Asp180Gly). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with TNNI3-related conditions (PMID: 20215591, 21483645, 21533915, 23785128, 30847666, 31112419, 31737537). ClinVar contains an entry for this variant (Variation ID: 403557). 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. 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. -

Cardiovascular phenotype Uncertain:1

Sep 25, 2019

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.D180G variant (also known as c.539A>G), located in coding exon 7 of the TNNI3 gene, results from an A to G substitution at nucleotide position 539. The aspartic acid at codon 180 is replaced by glycine, an amino acid with some similar properties. This variant has been reported in subjects with dilated cardiomyopathy (DCM) and left ventricular non-compaction (LVNC) (Hershberger RE, Circ Cardiovasc Genet 2010 Apr; 3(2):155-61; Hoedemaekers YM, Circ Cardiovasc Genet 2010 Jun; 3(3):232-9; Rampersaud E, Prog. Pediatr. Cardiol. 2011 Jan; 31(1):39-47). This variant was identified in one individual with DCM, but was not seen in the mother who also had features of DCM (Mook OR, J. Med. Genet. 2013 Sep; 50(9):614-26). This variant was also identified in a subject with LVNC, but was not seen in a maternal aunt who also had features of LVNC (Hoedemaekers YM, Circ Cardiovasc Genet 2010 Jun; 3(3):232-9). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on available evidence to date, the clinical significance of this variant remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.45
CardioboostCm	Pathogenic	0.99
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.88	D;T
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.96	D;D
M_CAP	Pathogenic	0.43	D
MetaRNN	Uncertain	0.73	D;D
MetaSVM	Uncertain	0.79	D
MutationAssessor	Benign	1.8	L;.
PrimateAI	Uncertain	0.73	T
PROVEAN	Uncertain	-4.4	D;.
REVEL	Pathogenic	0.69
Sift	Benign	0.065	T;.
Sift4G	Benign	0.062	T;T
Polyphen		0.99	D;.
Vest4		0.56
MutPred		0.32		Loss of helix (P = 0.0167);.;
MVP		0.97
MPC		1.6
ClinPred		0.99	D
GERP RS		4.7
Varity_R		0.87

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.20		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.20		Position offset: 14

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1060499912; hg19: chr19-55665408;