rs1060503103

Variant names:

• chr19-55154041-C-T
• rs1060503103
• NM_000363.5:c.538G>A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PM5

The NM_000363.5(TNNI3):​c.538G>A​(p.Asp180Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D180G) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 30)
• Consequence: TNNI3 NM_000363.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 7.82

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 Likely_pathogenic. Variant got 6 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
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr19-55154040-T-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNNI3	NM_000363.5	c.538G>A	p.Asp180Asn	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.538G>A	p.Asp180Asn	missense_variant	Exon 7 of 8	1	NM_000363.5	ENSP00000341838.5

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 30

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Primary dilated cardiomyopathy Uncertain:1

Jun 04, 2019

Agnes Ginges Centre for Molecular Cardiology, Centenary Institute

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: research

TNNI3 Asp180Asn has been previously reported in a childhood DCM case (Genedx, ClinVar: SCV000551897.1). We identified this variant in one DCM proband, the variant was also found to segregate to an affected family member. This variant is absent from the Genome Aggregation Database (http://gnomad.broadinstitute.org/). In silico tools SIFT, PolyPhen-2 and MutationTaster predict this variant to be deleterious. In summary, the variant has been reported in one other DCM case, is rare in the general population and in silico tools predict that the variant impacts protein function, therefore we classify TNNI3 Asp180Asn as a variant of 'uncertain significance'. -

Hypertrophic cardiomyopathy Uncertain:1

Sep 11, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, this variant is a novel missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C15"). This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a TNNI3-related disease. This sequence change replaces aspartic acid with asparagine at codon 180 of the TNNI3 protein (p.Asp180Asn). The aspartic acid residue is highly conserved and there is a small physicochemical difference between aspartic acid and asparagine. -

Cardiovascular phenotype Uncertain:1

Jul 07, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.D180N variant (also known as c.538G>A), located in coding exon 7 of the TNNI3 gene, results from a G to A substitution at nucleotide position 538. The aspartic acid at codon 180 is replaced by asparagine, an amino acid with highly similar properties. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.34
CardioboostCm	Pathogenic	1.0
BayesDel_addAF	Uncertain	0.096	D
BayesDel_noAF	Benign	-0.10
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.77	D;T
Eigen	Uncertain	0.68
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.96	D;D
M_CAP	Uncertain	0.28	D
MetaRNN	Uncertain	0.57	D;D
MetaSVM	Pathogenic	0.87	D
MutationAssessor	Uncertain	2.1	M;.
PrimateAI	Uncertain	0.76	T
PROVEAN	Uncertain	-3.1	D;.
REVEL	Uncertain	0.59
Sift	Benign	0.035	D;.
Sift4G	Uncertain	0.050	T;T
Polyphen		1.0	D;.
Vest4		0.45
MutPred		0.28		Gain of MoRF binding (P = 0.0306);.;
MVP		0.97
MPC		1.2
ClinPred		0.98	D
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.81

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs1060503103; hg19: chr19-55665409;