rs727503503

chr19-55154070-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000363.5(TNNI3):c.509G>A(p.Arg170Gln) variant causes a missense change. 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R170G) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TNNI3 NM_000363.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 6.04

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 Pathogenic. Variant got 18 ACMG points.

• PM1: In a hotspot region, there are 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 16 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 chr19-55154071-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 179285.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.981
• PP5: Variant 19-55154070-C-T is Pathogenic according to our data. Variant chr19-55154070-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 165516.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-55154070-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TNNI3	NM_000363.5	c.509G>A	p.Arg170Gln	missense_variant	7/8	ENST00000344887.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TNNI3	ENST00000344887.10	c.509G>A	p.Arg170Gln	missense_variant	7/8	1	NM_000363.5	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1460680 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 726680

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Likely pathogenic, no assertion criteria provided	clinical testing	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Oct 16, 2013	Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. p.Arg170Gln (c.509 G>A) in the TNNI3 gene We have seen this variant in a patient diagnosed at age 3 with RCM, s/p heart transplant. p.Arg170Gln has been reported in 1 pediatric HCM proband (Kaski 2009) and at the testing lab has been seen it in 7 individuals with early-onset RCM (including our patient). Two were de novo. TNNI3 is a gene strongly associated with RCM (Kubo 2007). This variant was not identified in large population studies, also supporting pathogenicity. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 02, 2021	Not observed in large population cohorts (Lek et al., 2016); Reported as pathogenic in ClinVar (ClinVar Variant ID #165516; Landrum et al., 2016); 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: 27532257, 28031081, 20031618, 31737537, 33336002, 32420109, 25940119) -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Aug 08, 2023	- -

Hypertrophic cardiomyopathy;C0007196:Restrictive cardiomyopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 04, 2015

The p.Arg170Gln variant in TNNI3 has been reported in 1 child with HCM (Kaski 20 09) and was identified by our laboratory in 6 individuals with early onset RCM, including 3 de novo occurrences (LMM unpublished data). This variant was absent from large population studies. Of note, RCM is thought to represent a rare prese ntation of the clinical spectrum of HCM and has so far been associated with vari ants in the MYH7 and TNNI3 genes (Kubo 2007). In summary, this variant meets ou r criteria to be classified as pathogenic for RCM in an autosomal dominant manne r based on multiple de novo occurrences in individuals with RCM. -

Hypertrophic cardiomyopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Feb 18, 2023

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 170 of the TNNI3 protein (p.Arg170Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 20031618, 25940119, 27532257). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 165516). 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. For these reasons, this variant has been classified as Pathogenic. -

Cardiovascular phenotype Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 06, 2023

The p.R170Q variant (also known as c.509G>A), located in coding exon 7 of the TNNI3 gene, results from a G to A substitution at nucleotide position 509. The arginine at codon 170 is replaced by glutamine, an amino acid with highly similar properties. This alteration has been reported in multiple individuals with hypertrophic cardiomyopathy (HCM) and restrictive cardiomyopathy (RCM), including a de novo occurrence in an individual with RCM (Kaski JP et al. Circ Cardiovasc Genet, 2009 Oct;2:436-41; Mouton JM et al. Cardiovasc J Afr, 2015;26:63-9; Ross SB et al. Circ Cardiovasc Genet, 2017 Jun;10:[ePub ahead of print]; Walsh R et al. Genet Med, 2017 Feb;19:192-203; Marschall C et al. Cardiovasc Diagn Ther, 2019 Oct;9:S292-S298; Marey I et al. Open Med (Wars), 2020 May;15:435-446; Stava TT et al. Eur J Prev Cardiol, 2022 Oct;29:1789-1799). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this variant is expected to be causative of autosomal dominant TNNI3-related cardiomyopathy; however, its clinical significance for autosomal recessive TNNI3-related dilated cardiomyopathy is unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.67
CardioboostCm	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.33
Cadd	Pathogenic	29
Dann	Pathogenic	1.0
DEOGEN2	Pathogenic	0.96	D;D
Eigen	Pathogenic	0.71
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Pathogenic	1.0	D;D
M_CAP	Pathogenic	0.60	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.3	M;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.66	T
PROVEAN	Uncertain	-3.5	D;.
REVEL	Pathogenic	0.88
Sift	Uncertain	0.0010	D;.
Sift4G	Uncertain	0.0030	D;D
Polyphen		1.0	D;.
Vest4		0.95
MutPred		0.85		Loss of MoRF binding (P = 0.0159);.;
MVP		0.97
MPC		1.8
ClinPred		1.0	D
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.97

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

Publications

LitVar

Other links and lift over

dbSNP: rs727503503; hg19: chr19-55665438; COSMIC: COSV52571562; COSMIC: COSV52571562;