rs368861241

chr19-55154095-G-Achr19-55154095-G-Cchr19-55154095-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM5PP3_ModeratePP5

The NM_000363.5(TNNI3):c.484C>T(p.Arg162Trp) variant causes a missense change. The variant allele was found at a frequency of 0.0000229 in 1,612,806 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R162P) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000025 ( 0 hom. )

Consequence

TNNI3
NM_000363.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:14U:2

Conservation

PhyloP100: 3.73

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

PM1

In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 13 uncertain in NM_000363.5

PM5

Other missense variant is known to change same aminoacid residue: Variant chr19-55154094-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 43390.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.883

PP5

Variant 19-55154095-G-A is Pathogenic according to our data. Variant chr19-55154095-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 161396.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=7, Uncertain_significance=1, Pathogenic=4}. Variant chr19-55154095-G-A is described in Lovd as [Pathogenic]. Variant chr19-55154095-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TNNI3	NM_000363.5 linkuse as main transcript	c.484C>T	p.Arg162Trp	missense_variant	7/8	ENST00000344887.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TNNI3	ENST00000344887.10 linkuse as main transcript	c.484C>T	p.Arg162Trp	missense_variant	7/8	1	NM_000363.5	P1

Frequencies

GnomAD3 genomes

AF:

0.00000659

AC:

AN:

151844

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000402

AC:

AN:

249000

Hom.:

AF XY:

0.0000444

AC XY:

AN XY:

135190

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000167

Gnomad SAS exome

AF:

0.0000980

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000265

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000246

AC:

AN:

1460962

Hom.:

Cov.:

AF XY:

0.0000303

AC XY:

AN XY:

726840

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000139

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000198

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000659

AC:

AN:

151844

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74126

show subpopulations

Gnomad4 AFR

AF:

0.00

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:

0.0000147

Gnomad4 OTH

AF:

0.00

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000120

AC:

ExAC

AF:

0.0000331

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:14Uncertain:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hypertrophic cardiomyopathy 7

Pathogenic:4Uncertain:1

Pathogenic, no assertion criteria provided	clinical testing	Clinical Laboratory Sciences Program (CLSP), King Saud bin Abdulaziz University for Health Sciences (KSAU-HS)	Apr 01, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	Jan 30, 2018	This c.484C>T (p.Arg162Trp) variant in the TNNI3 gene has been reported in multiple HCM patients with significantly higher prevalence [PMID: 9241277,21799269,21896538,22429680] than that observed as extremely low in general population according to gnomad database. Arginine at amino acid position 162 is highly conserved during evolution. Other amino acid changes at this or nearby positions have been reported in HCM patients as deleterious mutations [PMID: 27385602, 12860912, 21310275, 25611685, 27532257]. Functional studies showed that this mutant causes increased calcium sensitivity of cardiac muscle contraction and other alterations [PMID: 11735257, 10806205]. Homozygotes of this variant have been observed in two affected siblings with HCM while heterozygous carriers in this family are all normal. Multiple in silico predictions suggest this arginine to histidine change is deleterious. Based upon above evidences, this c.484C>T (p.Arg162Trp) variant in the TNNI3 gene is classified as pathogenic. -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Apr 04, 2024	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Region Ostergotland	Nov 15, 2023	- -
Likely pathogenic, criteria provided, single submitter	research	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Dec 03, 2018	The heterozygous p.Arg162Trp variant in TNNI3 was identified by our study in one individual with hypertrophic cardiomyopathy. This variant has been identified in 0.004071% (10/245660) of chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs368861241). Please note that for diseases like hypertrophic cardiomyopathy with clinical variability, or reduced penetrance, pathogenic variants may be present at a low frequency in the general population. This variant has been reported likely pathogenic or pathogenic in ClinVar (Variation ID: 161396). Two additional missense variants that affect the Arginine (Arg) at position 162 have been reported likely pathogenic or pathogenic in ClinVar, suggesting that a change in this position would not be tolerated (Variation ID: 43390, 43389). The p.Arg162Trp variant in TNNI3 has been reported in 12 individuals (6 Middle Eastern, 6 unknown) and segregated with disease in the homozygous state in 4 affected relatives from 2 families. The 6 clinically unaffected individuals from these 2 families were heterozygous for the variant, though this disease is known to have clinical variability (PMID: 24113344, 23270746). Four additional, unrelated individuals with this variant and hypertrophic cardiomyopathy have been reported in the literature (PMID: 22429680, 21799269). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In vitro functional studies provide some evidence that the p.Arg162Trp variant may impact protein function by reducing inhibition of actin-tropomyosin-activated myosin ATPase and increased calcium sensitivity in enzyme activity regulation (PMID: 11735257, 10806205). However, these types of assays may not accurately represent biological function. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PP1, PP3, PM2, PM5, PS3_Supporting (Richards 2015). -

Hypertrophic cardiomyopathy

Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 162 of the TNNI3 protein (p.Arg162Trp). This variant is present in population databases (rs368861241, gnomAD 0.02%). This missense change has been observed in individuals with hypertrophic cardiomyopathy, in the heterozygous and homozygous states (PMID: 9241277, 21799269, 21896538, 22429680, 25132132, 27532257, 28356264, 30847666, 32746448, 33673806). ClinVar contains an entry for this variant (Variation ID: 161396). 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. Experimental studies have shown that this missense change affects TNNI3 function (PMID: 10806205, 11735257). This variant disrupts the p.Arg162 amino acid residue in TNNI3. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12860912, 15607392, 15698845, 15992656, 16352453, 22876777). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, no assertion criteria provided	research	Agnes Ginges Centre for Molecular Cardiology, Centenary Institute	Mar 23, 2020	TNNI3 p.Arg162Trp was identified as a homozygous variant in 1 HCM proband as part of our research program. The proband came from a consanguineous family of Middle Eastern descent. An affected sibling was also found to have this homozygous variant. For further information please feel free to contact us. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Oct 08, 2020	The p.Arg162Trp variant in TNNI3 has been reported in the heterozygous state in >10 individuals with hypertrophic cardiomyopathy (HCM; Kimura 1997 PMID: 9241277; Garcia-Pavia 2011 PMID: 21896538; Kubo 2011 PMID: 21799269; Gomez 2017 PMID: 28356264; Walsh 2017 PMID: 27532257; LMM data). It was also identified in the homozygous state in 1 Indian and 1 Jordanian individuals with HCM and segregated with disease in the homozygous state in 3 affected relatives, but none of the heterozygous relatives (<50 years old) were affected (Gray 2013 PMID: 23270746; Das 2014 PMID: 24113344; LMM data). The variant has also been reported by other clinical laboratories in ClinVar (Variation ID: 161396) and was identified in 0.003% (3/113182) of European chromosomes and 0.02% (3/17978) of East Asian chromosomes by gnomAD (http://gnomad.broadinstitute.org). In vitro functional studies provide some evidence that the p.Arg162Trp variant may impact protein function (Elliott 2000 PMID: 10806205; Takahashi-Yanaga 2001 PMID: 11735257). Computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. Moreover, two other variants have been identified at this position (p.Arg162Pro, p.Arg162Gln) and have been classified by this laboratory as likely pathogenic, suggesting changes at this position are not tolerated. The available data on the p.Arg162Gln suggests that it may be a mild variant, with reduced penetrance. In summary, the p.Arg162Trp variant is likely pathogenic; however, this variant may have a milder role suggested by the incomplete penetrance seen in some family members and the individuals who were homozygous, similar to that observed for p.Arg162Gln. ACMG/AMP Criteria applied: PS4_Moderate, PM2_Supporting, PM5_Supporting, PP1, PS3_Supporting. -
Likely pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Jan 06, 2024	This missense variant replaces arginine with tryptophan at codon 162 of the TNNI3 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Functional studies have shown that this variant increases the Ca2+ sensitivity of cardiac muscle contraction (PMID: 10806205, 11735257). This variant has been reported in over ten individuals affected with hypertrophic cardiomyopathy (PMID: 9241277, 21799269, 21896538, 22429680, 24113344, 27532257, 30105547, 30847666, 32746448, 33495596, 33495597, 33673806). In one family, this variant was observed in homozygosity in two siblings affected with hypertrophic cardiomyopathy (PMID: 24113344). However, four heterozygous carriers from this family were not clinically affected. This variant has been identified in 10/249000 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Different missense variants occurring at this codon, p.Arg162Pro and p.Arg162Gln, are considered to be disease-causing (ClinVar variant ID: 43390 and 43389), suggesting that arginine at this position is important for TNNI3 protein function. Based on the available evidence, this variant is classified as Likely Pathogenic. -

Cardiomyopathy

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	May 09, 2023	This missense variant replaces arginine with tryptophan at codon 162 of the TNNI3 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Functional studies have shown that this variant increases the Ca2+ sensitivity of cardiac muscle contraction (PMID: 10806205, 11735257). This variant has been reported in over ten individuals affected with hypertrophic cardiomyopathy (PMID: 9241277, 21799269, 21896538, 22429680, 24113344, 27532257, 30105547, 30847666, 32746448, 33495596, 33495597, 33673806). In one family, this variant was observed in homozygosity in two siblings affected with hypertrophic cardiomyopathy (PMID: 24113344). However, four heterozygous carriers from this family were not clinically affected. This variant has been identified in 10/249000 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Different missense variants occurring at this codon, p.Arg162Pro and p.Arg162Gln, are considered to be disease-causing (ClinVar variant ID: 43390 and 43389), suggesting that arginine at this position is important for TNNI3 protein function. Based on the available evidence, this variant is classified as Likely Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Jan 24, 2023	- -

Cardiovascular phenotype

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Oct 20, 2023	The p.R162W variant (also known as c.484C>T), located in coding exon 7 of the TNNI3 gene, results from a C to T substitution at nucleotide position 484. The arginine at codon 162 is replaced by tryptophan, an amino acid with dissimilar properties. This variant has been reported in the heterozygous state in multiple individuals with hypertrophic cardiomyopathy (HCM) (Kimura A et al. Nat. Genet. 1997;16:379-82; Garcia-Pavia P et al. Eur. J. Heart Fail. 2011;13:1193-201; Santos S et al. BMC Med. Genet. 2012;13:17; Gómez J et al. Circ. J. 2014;78:2963-71 Lopes LR et al. Heart. 2015;101:294-301; Walsh R et al. Genet. Med. 2017;19:192-203). This alteration has also been detected in a pediatric cardiomyopathy cohort It has also been detected in the homozygous state in two siblings and a third, unrelated individual with HCM; however, their heterozygous relatives were unaffected (Das K J et al. Genet. Med. 2014;16:286-93; Gray B et al. Int. J. Cardiol. 2013;168:1530-1). This variant has also been seen in an exome cohort, but cardiovascular history was not provided (Amendola LM et al. Genome Res. 2015;25:305-15). Functional studies suggest that this alteration impacts TNNI3 protein function (Elliott K et al. J. Biol. Chem. 2000;275:22069-74; Takahashi-Yanaga F et al. J. Mol. Cell. Cardiol. 2001;33:2095-107). Another alteration at the same codon, p.R162Q (c.485G>A), has been described in association with HCM (Van Driest SL et al. Circulation. 2003;108(4):445-51). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. 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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 27, 2018	Variant summary: TNNI3 c.484C>T (p.Arg162Trp) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function and a different missense mutation at this same residue (p.Arg162Gln) has been internally classified as Likely Pathogenic, suggesting that changes at Arg162 are not tolerated. Additionally, several functional studies indicate that this variant reduces the apparent affinity of cTnI for actin without changing the intrinsic inhibitory activity, and induces a definite increase in the Ca2+- sensitivitiy of myofibrillar ATPase activity and force generation in skinned muscle fibers. It has been suggested that the decreased inhibition and increased calcium sensitivity may cause HCM via impaired relaxation rather than the impaired contraction seen with some other classes of HCM mutants (Elliott_2000). The variant allele was found at a frequency of 4e-05 in 247390 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in LMM reportedly detected the variant in 4 individuals with HCM (1 Caucasian adult, 2 Indian adolescents, and 1 Jordanian adolescent). Several reported HCM patients in the literature (Kimura_1997, Garcia-Pavia_ 2011, Wang_2014, etc), and two individuals reported by LMM laboratory, were all heterozygous for the variant of interest, which is consistent with dominant inheritance. However, the variant has also been reported in two non-Caucasian families (one Indian and one Jordanian reported by LMM) and one Middle Eastern family (Gray_TNNI3_Int J Cardiol_2013) with 5 affected individuals being homozygous from the 3 families and none of the heterozygous family members being affected. This may suggest that c.484C>T is either a mild variant with reduced penetrance, and/or co-dominant effect is required to develop clinical features; recessive mode of inheritance cannot be completely ruled out. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Apr 25, 2022

Reported in the homozygous state in both a proband with HCM with features of a restrictive process and her brother with classic HCM; autosomal recessive inheritance was proposed as the four individuals heterozygous for the variant (both parents and two siblings) were clinically unaffected (Gray et al., 2013); Published functional studies demonstrate that this variant interferes with normal troponin function and is expected to impair cardiac muscle relaxation (Elliott et al., 2000; Takahashi-Yanaga et al., 2001); 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: 23299917, 24113344, 20298698, 20350521, 25351510, 15992656, 29551499, 29203298, 11735257, 23270746, 25637381, 10615387, 23840593, 25342278, 21967901, 22429680, 21839045, 21799269, 9241277, 27532257, 25649125, 15607392, 22876777, 15698845, 15070570, 25132132, 30105547, 32686758, 32830170, 28356264, 32746448, 33673806, 30847666, 31447099, 21896538, 10806205, 33487615) -

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

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Aug 14, 2021

- -

Primary familial hypertrophic cardiomyopathy

Uncertain:1

Uncertain significance, no assertion criteria provided

research

CSER _CC_NCGL, University of Washington

Jun 01, 2014

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.41

CardioboostCm

Uncertain

0.64

BayesDel_addAF

Benign

-0.055

BayesDel_noAF

Uncertain

-0.050

Cadd

Pathogenic

Dann

Pathogenic

1.0

DEOGEN2

Pathogenic

0.94

D;D

Eigen

Uncertain

0.34

Eigen_PC

Uncertain

0.34

FATHMM_MKL

Uncertain

0.81

LIST_S2

Pathogenic

0.97

D;D

M_CAP

Pathogenic

0.46

MetaRNN

Pathogenic

0.88

D;D

MetaSVM

Uncertain

0.50

MutationAssessor

Benign

1.4

L;.

MutationTaster

Benign

0.99

D;D

PrimateAI

Uncertain

0.67

PROVEAN

Pathogenic

-4.9

D;.

REVEL

Pathogenic

0.67

Sift

Pathogenic

0.0

D;.

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

D;.

Vest4

0.80

MVP

0.95

MPC

1.6

ClinPred

0.73

GERP RS

3.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.81

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

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