chr19-55154157-C-T

Position:

chr19-55154157-C-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM5PP3_StrongPP5_Very_Strong

The NM_000363.5(TNNI3):c.422G>A(p.Arg141Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000682 in 1,613,100 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R141W) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

TNNI3
NM_000363.5 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:15

Conservation

PhyloP100: 1.74

Variant links:

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 links:

TNNI3 (HGNC:):

TNNI3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PM1

In a region_of_interest Involved in binding TNC and actin (size 20) in uniprot entity TNNI3_HUMAN there are 16 pathogenic changes around while only 0 benign (100%) in NM_000363.5

PM5

Other missense variant is known to change same aminoacid residue: Variant chr19-55154158-G-A is described in Lovd as [Likely_pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.981

PP5

Variant 19-55154157-C-T is Pathogenic according to our data. Variant chr19-55154157-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 43381.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-55154157-C-T is described in Lovd as [Pathogenic]. Variant chr19-55154157-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TNNI3	NM_000363.5 linkuse as main transcript	c.422G>A	p.Arg141Gln	missense_variant	7/8	ENST00000344887.10	NP_000354.4	P19429Q6FGX2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TNNI3	ENST00000344887.10 linkuse as main transcript	c.422G>A	p.Arg141Gln	missense_variant	7/8	1	NM_000363.5	ENSP00000341838.5		P19429

Frequencies

GnomAD3 genomes

AF:

0.0000395

AC:

AN:

152042

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000966

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000342

AC:

AN:

1461058

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

726834

show subpopulations

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:

0.00000360

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000395

AC:

AN:

152042

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74252

show subpopulations

Gnomad4 AFR

AF:

0.0000966

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000302

EpiCase

AF:

0.000109

EpiControl

AF:

0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:15

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:4

Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Dec 12, 2014	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.Arg141Gln (c.422 G>A) in the TNNI3 gene (NM_000363.4). Given the strong case data and absence in the general population (reviewed below) we consider this variant likely disease causing. The variant has been seen in at least 11 unrelated cases of HCM (not including this patient's family). There is only weak segregation data available from one family. Richard et al (2003) observed the variant in one patient with HCM from their 197 patient French cohort that underwent sequencing of multiple sarcomere genes. van Driest et al (2003) observed the variant in one patient with HCM from their 389 patient cohort recruited at Mayo. He was diagnosed at 27 years of age. Mogenson et al (2004) observed the variant in two HCM patients from their cohort of 748 HCM patients cared for by Bill McKenna's group at St. George's hospital in London. One patient was actually homozygous for the variant. That patient was noted to have a particularly severe presentation with biventricular hypertrophy. Family members were not available to be evaluated but there was concerning family history. Morita et al (2008) observed the variant in one HCM patient in a cohort of 84 pediatric HCM cases from the pediatric cardiomyopathy registry (recruited throughout North America). The patient also carried p.Arg495Gln in MYBPC3 (we have reviewed this variant and classify it as likely disease causing). Individual phenotypic details were not available (though onset was pediatric in all cases). Rani et al (2012) sequenced just TNNI3 in 101 patients with HCM from their South Indian cohort and observed this variant in two patients. They do not explicitly state that the patients were all unrelated, though presumably they were. Santos et al (2012) observed the variant in one HCM patient from their Portuguese cohort of 80 HCM patients. Curila et al (2009) observed the variant in 2 patients with HCM in their Czech cohort of 101 HCM patients. In one family it segregated with disease in 2 affected first degree relatives. van den Wijngaard et al (2011) observed the variant in a patient with HCM from a large cohort of 1040 HCM patients pooled from clinics across the Netherlands. Ramachandran et al (2013) studied this variant in silico and found it altered local protein structure and changed intra and intermolecular hydrogen bonding patterns. In silico analysis with PolyPhen-2 predicts the variant to be probably damaging (score 0.975) and SIFT predicts it to be deleterious. The Grantham score is 43. The arginine at codon 141 is completely conserved across mammals, as are neighboring amino acids. Other variants have been reported in association with disease at nearby codons (Arg145Gln, Arg145Gly, Arg144Gln, Arg144Pro). I could not find another variant at the same codon. The variant falls in the troponin C binding domain. Of note, there are a lot of variants in patients in this region but none to few in general population samples like NHLBI ESP. In total the variant has not been seen in 7310 laboratory controls, published controls and individuals from publicly available population datasets. There is no variation at codon 141 listed in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~6500 Caucasian and African American individuals (as of April 8th, 2014). There is also no variation at this codon listed in dbSNP (as of April 8th, 2014). The variant was not observed in the following laboratory and published control samples: 200 healthy individuals analyzed by GeneDx, 100 healthy individuals (Richard et al 2003), 200 healthy individuals (van Driest et al 2003), 160 healthy individuals from South India (Deepa et al 2012), 150 healthy individu -
Likely pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 15, 2021	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: 15524171, 18227814, 21533915, 24510615, 25351510, 22429680, 12707239, 12860912, 18403758, 19645627, 22876777, 22455086, 23283745, 25524337, 23967088, 27532257, 15607392, 31727422, 31737537, 31447099, 33087929, 34428338, 33673806, 26582918) -

Hypertrophic cardiomyopathy

Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jul 26, 2019	The p.Arg141Gln variant in TNNI3 has been reported in >25 individuals with hypertrophic cardiomyopathy (HCM) and segregated with disease in 3 affected relatives from 3 families (Richard 2003, Van Driest 2003, Mogensen 2004, Morita 2008, Curila 2009, van den Wijngaard 2011, Rani 2012, Santos 2012, Kapplinger 2014, Walsh 2017, Invitae pers. comm., LMM data). It was also identified in the homozygous state in an individual with a severe HCM presentation (Mogensen 2004) and in 2 individuals with early-onset HCM who had an additional variant in an HCM-associated gene (MYBPC3, TNNT2) that was likely contributing to disease (Morita 2008, LMM data, Santos 2012). Additionally, this variant has been reported by other clinical laboratories in ClinVar (Variation ID 43381) and has also been identified in 1/8710 of African chromosomes by gnomAD (http://gnomad.broadinstitute.org/). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant HCM. ACMG/AMP Criteria applied: PS4_Very Strong, PP1, PM2. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	Jul 07, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 03, 2024	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 141 of the TNNI3 protein (p.Arg141Gln). This variant is present in population databases (rs397516347, gnomAD 0.01%). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 12707239, 15607392, 18403758, 19645627, 22429680, 22876777, 23283745, 25524337). ClinVar contains an entry for this variant (Variation ID: 43381). 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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Sep 27, 2024	This missense variant is located in the inhibitory, actin binding region of the TNNI3 protein. Computational prediction tools and conservation analyses suggest that this variant may have deleterious impact on the protein function. Computational splicing tools suggest that this variant may not impact the RNA splicing. To our knowledge, functional assays have not been performed for this variant. This variant has been reported in more than ten individuals affected with hypertrophic cardiomyopathy (PMID: 12707239, 18403758, 23283745, 19645627, 22429680, 25524337, 22876777), including a homozygous individual who showed a severe phenotype (PMID: 15607392). This variant has been identified in 1/30938 chromosomes by the Genome Aggregation Database (gnomAD). Based on available evidence, this variant is classified as Likely Pathogenic. -

Cardiomyopathy

Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 22, 2019	This missense variant is located in the inhibitory, actin binding region of the TNNI3 protein. Computational prediction tools and conservation analyses suggest that this variant may have deleterious impact on the protein function. Computational splicing tools suggest that this variant may not impact the RNA splicing. To our knowledge, functional assays have not been performed for this variant. This variant has been reported in more than ten individuals affected with hypertrophic cardiomyopathy (PMID: 12707239, 18403758, 23283745, 19645627, 22429680, 25524337, 22876777), including a homozygous individual who showed a severe phenotype (PMID: 15607392). This variant has been identified in 1/30938 chromosomes by the Genome Aggregation Database (gnomAD). Based on available evidence, this variant is classified as Likely Pathogenic. -
Likely pathogenic, no assertion criteria provided	clinical testing	Institute of Human Genetics, University of Wuerzburg	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Mar 20, 2020	- -

Hypertrophic cardiomyopathy 7;C1861861:Cardiomyopathy, familial restrictive, 1;C2678474:Dilated cardiomyopathy 2A;C2750091:Dilated cardiomyopathy 1FF

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jul 28, 2021	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	Mar 30, 2021	TNNI3 NM_000363.4 exon 7 p.Arg141Gln (c.422G>A): This variant has been reported in the literature in several individuals with HCM, including once in the homozygous state (Richard 2003 PMID:12707239, Van Driest 2003 PMID:12860912, Morgensen 2004 PMID:15607392, Santos 2012 PMID:22429680, Rani 2012 PMID:22876777, Ramachandran 2013 PMID:23967088, Walsh 2017 PMID:27532257). This variant also segregated with disease in one family (Curila 2009 PMID:19645627). This variant is present in 0.003% (1/31370) of total alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/variant/19-55665525-C-T). Please note, disease causing variants may be present in control databases at low frequencies, reflective of the general population, and/or variable expressivity. This variant is also present in ClinVar, with several labs classifying this variant as pathogenic or likely pathogenic (Variation ID:43381). Evolutionary conservation and computational predictive tools for this variant are unclear. In summary, data on this variant is highly suspicious for disease, but requires further evidence for pathogenicity. Therefore, this variant is classified as likely pathogenic. -

Hypertrophic cardiomyopathy 7

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

3billion

Mar 22, 2022

Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000043381, PMID:12707239). The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 12707239, 12860912, 18403758, 19645627, 27532257, 26440512). In silico tool predictions suggest damaging effect of the variant on gene or gene product (3CNET: 0.982>=0.75). A missense variant is a common mechanism. It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.0011792). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -

Cardiovascular phenotype

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 01, 2024

The c.422G>A (p.R141Q) alteration is located in exon 7 (coding exon 7) of the TNNI3 gene. This alteration results from a G to A substitution at nucleotide position 422, causing the arginine (R) at amino acid position 141 to be replaced by a glutamine (Q). for autosomal dominant TNNI3-related cardiomyopathy; however, its clinical significance for autosomal recessive TNNI3-related dilated cardiomyopathy is uncertain. This allele was reported in one heterozygous individual in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant was reported in multiple individuals with features consistent with TNNI3-related cardiomyopathy (Richard, 2003; Van Driest, 2003; van den Wijngaard, 2011; Landry, 2017). This variant was detected in the homozygous state in an individual with severe biventricular hypertrophy (Mogensen, 2004), and has co-occurred with other variants in cardiac-related genes in affected individuals, including an individual from a childhood-onset HCM cohort (Morita, 2008; Santos, 2012). This variant has been reported as de novo and shown segregation with disease (Curila, 2009); however, it has also been detected in unaffected relatives (Mogensen, 2004). This amino acid position is well conserved in available vertebrate species. Based on internal structural assessment, this alteration disrupts a well-established phosphorylation motif necessary for myofilament Ca2+ sensitivity and ATPase activity (Pi, 2003; Wang, 2012). The in silico prediction for this alteration is inconclusive. Based on the available evidence, this alteration is classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.69

CardioboostCm

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.17

BayesDel_noAF

Uncertain

0.010

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.96

D;D

Eigen

Uncertain

0.38

Eigen_PC

Uncertain

0.32

FATHMM_MKL

Benign

0.32

LIST_S2

Pathogenic

1.0

D;D

M_CAP

Uncertain

0.20

MetaRNN

Pathogenic

0.98

D;D

MetaSVM

Pathogenic

0.98

MutationAssessor

Uncertain

2.9

M;.

PrimateAI

Uncertain

0.62

PROVEAN

Uncertain

-2.8

D;.

REVEL

Uncertain

0.58

Sift

Uncertain

0.0030

D;.

Sift4G

Uncertain

0.0060

D;D

Polyphen

0.97

D;.

Vest4

0.87

MutPred

0.92

Loss of glycosylation at P142 (P = 0.086);.;

MVP

0.94

MPC

1.6

ClinPred

0.98

GERP RS

4.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.93

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over