rs267607129

chr19-55151912-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PM5 PP5

The NM_000363.5(TNNI3):c.555C>G(p.Asn185Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N185S) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TNNI3 NM_000363.5 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 1.10

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 7 ACMG points.

• PM1: In a hotspot region, there are 10 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 14 uncertain 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 chr19-55151913-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 181588.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP5: Variant 19-55151912-G-C is Pathogenic according to our data. Variant chr19-55151912-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 12431.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr19-55151912-G-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TNNI3	NM_000363.5	c.555C>G	p.Asn185Lys	missense_variant	8/8	ENST00000344887.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TNNI3	ENST00000344887.10	c.555C>G	p.Asn185Lys	missense_variant	8/8	1	NM_000363.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Dilated cardiomyopathy 1FF Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Aug 14, 2009

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
CardioboostCm	Uncertain	0.17
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.40
Cadd	Benign	17
Dann	Benign	0.66
DEOGEN2	Benign	0.34	T;T
Eigen	Benign	-0.73
Eigen_PC	Benign	-0.46
FATHMM_MKL	Benign	0.75	D
LIST_S2	Benign	0.60	T;T
M_CAP	Benign	0.083	D
MetaRNN	Uncertain	0.64	D;D
MetaSVM	Benign	-0.45	T
MutationAssessor	Benign	-0.81	N;.
MutationTaster	Benign	0.63	D;N
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	0.61	N;.
REVEL	Benign	0.23
Sift	Benign	1.0	T;.
Sift4G	Benign	1.0	T;T
Polyphen		0.0020	B;.
Vest4		0.76
MutPred		0.74		Gain of ubiquitination at N185 (P = 0.0155);.;
MVP		0.79
MPC		0.76
ClinPred		0.30	T
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.34

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs267607129; hg19: chr19-55663280;