NM_000363.5:c.579G>C

Variant names:

• chr19-55151888-C-G
• rs397516358
• NM_000363.5:c.579G>C

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PS1 PM1 PM2 PP3_Moderate

The NM_000363.5(TNNI3):​c.579G>C​(p.Lys193Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K193R) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TNNI3 NM_000363.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 2.38
• Publications: 2 publications found

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]

TNNI3 Gene-Disease associations (from GenCC):

• hypertrophic cardiomyopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• dilated cardiomyopathy 2A

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• hypertrophic cardiomyopathy 7

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), G2P
• cardiomyopathy, familial restrictive, 1

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• dilated cardiomyopathy 1FF

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• dilated cardiomyopathy

  Inheritance: AD Classification: MODERATE Submitted by: ClinGen
• familial isolated dilated cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• familial isolated restrictive cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• arrhythmogenic right ventricular cardiomyopathy

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PS1: Transcript NM_000363.5 (TNNI3) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• PM1: In a hotspot region, there are 16 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 26 uncertain in NM_000363.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.85

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000363.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNNI3	NM_000363.5	MANE Select	c.579G>C	p.Lys193Asn	missense	Exon 8 of 8	NP_000354.4

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNNI3	ENST00000344887.10	TSL:1 MANE Select	c.579G>C	p.Lys193Asn	missense	Exon 8 of 8	ENSP00000341838.5
	TNNI3	ENST00000665070.1		c.612G>C	p.Lys204Asn	missense	Exon 8 of 8	ENSP00000499482.1
	TNNI3	ENST00000714238.1		c.567G>C	p.Lys189Asn	missense	Exon 8 of 8	ENSP00000519518.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Apr 06, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant classified as Uncertain Significance - Favor Pathogenic. The Lys193Asn v ariant in TNNI3 has not been reported in the literature, but has been identified in 1 individual with HCM (this individual's son) out of >2,100 Caucasian proban ds tested by our laboratory. This low frequency is consistent with a pathogenic role. Computational analyses (biochemical amino acid properties, conservation, A lignGVGD, PolyPhen2, and SIFT) suggest that the Lys193Asn variant may impact the protein, though this information is not predictive enough to determine pathogen icity. Additional information is needed to fully assess the clinical significan ce of the Lys193Asn variant.

Hypertrophic cardiomyopathy Uncertain:1

Nov 12, 2015

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces lysine with asparagine at codon 193 of the TNNI3 protein (p.Lys193Asn). The lysine residue is highly conserved and there is a moderate physicochemical difference between lysine and asparagine. This variant is not present in population databases (rs397516358, ExAC no frequency). ClinVar contains an entry for this variant (Variation ID: 43396). This variant was observed in this patient's sibling who was diagnosed with hypertrophic cardiomyopathy, and was found to be absent in this patient's father. This patient's mother, who was affected with hypertrophic cardiomyopathy and had a family history consistent with inherited cardiovascular disease, was not genotyped. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies. This missense change is located in a region of the TNNI3 protein where a significant number of previously reported TNNI3 missense mutations are found (PMID: 15607392). These observations suggest that a previously unreported missense substitution within this region may affect protein function, but experiments have not been done to test this possibility. In summary, the observation in this family is suggestive of segregation with hypertrophic cardiomyopathy and this variant found in a region of the protein known to be important for protein function. However, the segregation evidence is limited and functional impact has not been confirmed at this time. For these reasons, this change has been classified as a Variant of Uncertain Significance.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
CardioboostCm	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.070
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.92	D
Eigen	Uncertain	0.29
Eigen_PC	Benign	0.19
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.95	D
M_CAP	Pathogenic	0.71	D
MetaRNN	Pathogenic	0.85	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.4	M
PhyloP100		2.4
PrimateAI	Pathogenic	0.81	D
PROVEAN	Uncertain	-4.0	D
REVEL	Pathogenic	0.80
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.72
MutPred		0.41		Loss of ubiquitination at K193 (P = 0.0107)
MVP		0.95
MPC		1.8
ClinPred		1.0	D
GERP RS		2.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.90
Mutation Taster		=1/99	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs397516358; hg19: chr19-55663256;