rs730881068

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1

The NM_000363.5(TNNI3):​c.292C>T​(p.Arg98*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000428 in 1,614,026 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. R98R) has been classified as Benign. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 31)
Exomes 𝑓: 0.000042 ( 0 hom. )

Consequence

TNNI3
NM_000363.5 stop_gained

Scores

1
5
1

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:9

Conservation

PhyloP100: 0.910
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
TNNI3NM_000363.5 linkc.292C>T p.Arg98* stop_gained Exon 6 of 8 ENST00000344887.10 NP_000354.4 P19429Q6FGX2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
TNNI3ENST00000344887.10 linkc.292C>T p.Arg98* stop_gained Exon 6 of 8 1 NM_000363.5 ENSP00000341838.5 P19429
ENSG00000267110ENST00000587871.1 linkn.*394C>T non_coding_transcript_exon_variant Exon 9 of 9 5 ENSP00000473050.1 M0R381
ENSG00000267110ENST00000587871.1 linkn.*394C>T 3_prime_UTR_variant Exon 9 of 9 5 ENSP00000473050.1 M0R381

Frequencies

GnomAD3 genomes
AF:
0.0000460
AC:
7
AN:
152202
Hom.:
0
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.0000241
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:
0.0000882
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000601
AC:
15
AN:
249396
Hom.:
0
AF XY:
0.0000813
AC XY:
11
AN XY:
135338
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000556
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.0000464
Gnomad NFE exome
AF:
0.000115
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000424
AC:
62
AN:
1461824
Hom.:
0
Cov.:
31
AF XY:
0.0000399
AC XY:
29
AN XY:
727208
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:
0.0000187
Gnomad4 NFE exome
AF:
0.0000504
Gnomad4 OTH exome
AF:
0.0000497
GnomAD4 genome
AF:
0.0000460
AC:
7
AN:
152202
Hom.:
0
Cov.:
31
AF XY:
0.0000404
AC XY:
3
AN XY:
74344
show subpopulations
Gnomad4 AFR
AF:
0.0000241
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:
0.0000882
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000494
Hom.:
0
Bravo
AF:
0.0000529
ExAC
AF:
0.0000908
AC:
11
EpiCase
AF:
0.0000545
EpiControl
AF:
0.00

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:9
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:3
Uncertain significance, criteria provided, single submitterclinical testingMayo Clinic Laboratories, Mayo ClinicJul 22, 2024PM3 -
Uncertain significance, criteria provided, single submitterclinical testingClinical Genetics Laboratory, Skane University Hospital LundMay 27, 2022- -
Uncertain significance, criteria provided, single submitterclinical testingGeneDxMay 26, 2023Reported in association with cardiomyopathy, however, additional clinical information was not provided (Walsh et al., 2017; Lu et al., 2018); Reported in a participant in the Framingham heart study (FHS) who had a normal left ventricular wall thickness and a physiological risk factor for heart disease (Bick et al., 2012); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is not a known mechanism of disease; This variant is associated with the following publications: (PMID: 22958901, 27532257, 28436080, 30165862) -
Hypertrophic cardiomyopathy Pathogenic:1Uncertain:1
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 14, 2025This sequence change creates a premature translational stop signal (p.Arg98*) in the TNNI3 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in TNNI3 are known to be pathogenic (PMID: 31568572, 34036930, 35838873). This variant is present in population databases (rs730881068, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with autosomal recessive dilated cardiomyopathy (PMID: 36252119, 36981019). ClinVar contains an entry for this variant (Variation ID: 181575). For these reasons, this variant has been classified as Pathogenic. -
Uncertain significance, criteria provided, single submitterclinical testingAll of Us Research Program, National Institutes of HealthJul 29, 2024This variant changes 1 nucleotide in exon 6 of the TNNI3 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. An experimental functional study has shown that this variant may cause reduced protein expression and increased Ca2+-sensitivity (PMID: 28436080). However, clinical relevance of this observation is not clear. This variant has been reported in several individuals affected with dilated cardiomyopathy (PMID: 28436080, 30165862, 34286374, 38795101), in one individual affected with hypertrophic cardiomyopathy (PMID: 27532257), and in a fetus affected with stillbirth (PMID: 30615648). This variant has also been reported in homozygosity in two infants affected with early-onset dilated cardiomyopathy (PMID: 36252119, 36981019); for both infants, both heterozygous parents were clinically unaffected. This variant has been identified in 16/280804 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Clinical relevance of loss-of-function TNNI3 truncation variants in autosomal dominant cardiovascular disorders is not clearly established. The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
Cardiomyopathy Uncertain:2
Uncertain significance, criteria provided, single submitterclinical testingColor Diagnostics, LLC DBA Color HealthMay 11, 2023This variant changes 1 nucleotide in exon 6 of the TNNI3 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. An experimental functional study has shown that this variant may cause reduced protein expression and increased Ca2+-sensitivity (PMID: 28436080). However, clinical relevance of this observation is not clear. This variant has been reported in individuals affected with dilated cardiomyopathy (PMID 28436080, 30165862, 34286374), in an individual affected with hypertrophic cardiomyopathy (PMID: 27532257), and in a fetus affected with stillbirth (PMID: 30615648). This variant has also been reported in homozygosity in an infant affected with early-onset dilated cardiomyopathy (PMID: 36981019); both heterozygous parents were apparently unaffected but did not receive cardiological evaluations. This variant has been identified in 16/280804 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Clinical relevance of loss-of-function TNNI3 truncation variants in autosomal dominant cardiovascular disorders is not clearly established. The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitterclinical testingCHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern OntarioApr 05, 2018- -
Hypertrophic cardiomyopathy 7;C1861861:Cardiomyopathy, familial restrictive, 1;C2678474:Dilated cardiomyopathy 2A;C2750091:Dilated cardiomyopathy 1FF Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsOct 29, 2021- -
Dilated cardiomyopathy 2A Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingVictorian Clinical Genetics Services, Murdoch Childrens Research InstituteJul 17, 2023Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3A. Following criteria are met: 0103 - Gain of function and loss of function are reported mechanisms of disease in this gene. Gain of function is associated with familial restrictive cardiomyopathy 1 (MIM#115210) and hypertrophic cardiomyopathy 7 (HCM; MIM#613690), while the latter is associated with dilated cardiomyopathy 1FF (DCM; MIM#613286) (PMIDs: 19914256, 21533915). (I) 0108 - This gene is associated with both recessive and dominant disease. The recessive form of inheritance is the exception and has only been reported in a few families (PMIDs: 15070570, 23270746, 31568572). (I) 0112 - The condition associated with this gene has incomplete penetrance (PMID: 15607392). (I) 0115 - Variants in this gene are known to have variable expressivity (PMID: 23270746). (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0252 - This variant is homozygous. (I) 0302 - Variant is present in gnomAD (v2) <0.001 for a dominant condition (16 heterozygotes, 0 homozygotes). (SP) 0708 - Other NMD variants comparable to the one identified in this case have conflicting previous evidence for pathogenicity. Most NMD variants reported in patients with cardiomyopathies are either VUS or conflicting, however p.(Asp113Alafs*2) has been regarded pathogenic for HCM (PMID: 27532257) and p.(Arg69Alafs*8) has been reported in a family with recessive DCM (PMID: 31568572). (I) 0808 - Previous reports of pathogenicity for this variant are conflicting. This variant has been reported as VUS, likely pathogenic and pathogenic (ClinVar, LOVD) in individuals with HCM (PMID: 27532257) or DCM (PMID: 28436080, 30065175, 30165862). It has also been detected in a case of stillbirth in a study screening heart disease genes (PMID: 30615648). (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Heart biopsy of a patient with DCM showed increased calcium sensitivity and decreased length-dependent activation. In addition, this variant was shown to reduce expression of the troponin complex proteins and altered stoichiometry between the subunits. Exchange with wild-type troponin complex corrected troponin protein levels to 83% of controls (PMID: 28436080). (SP) 1209 - This variant has been shown to be both maternally and paternally inherited (biallelic) (by segregation analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsApr 16, 2024The p.R98* variant (also known as c.292C>T), located in coding exon 6 of the TNNI3 gene, results from a C to T substitution at nucleotide position 292. This changes the amino acid from an arginine to a stop codon within coding exon 6. This variant has been reported in individual(s) from dilated cardiomyopathy (DCM) and hypertrophic cardiomyopathy (HCM) cohorts, but clinical details were limited (Bollen IAE et al. J Physiol, 2017 Jul;595:4677-4693; Walsh R et al. Genet Med, 2017 Feb;19:192-203; Lu C et al. J Transl Med, 2018 Aug;16:241; Gran F et al. Eur J Pediatr, 2022 Jan;181:287-294). This variant has been identified in the homozygous state in individual(s) with features consistent with pediatric-onset dilated cardiomyopathy whose heterozygous relatives were reportedly unaffected (Bagnall RD. Circ Genom Precis Med. 2022 Dec;15(6):e003686; Sorrentino U. Genes (Basel). 2023 Mar;14(3)). Functional studies from one group suggest this variant may alter calcium sensitivity; however, the physiological relevance of this finding is unclear (Bollen IAE et al. J Physiol, 2017 Jul;595:4677-4693). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. Although biallelic loss of function of TNNI3 has been associated with autosomal recessive dilated cardiomyopathy, haploinsufficiency of TNNI3 has not been established as a mechanism of disease for autosomal dominant cardiomyopathy. Based on the supporting evidence, this variant is expected to be causative of autosomal recessive dilated cardiomyopathy when present along with a second pathogenic variant on the other allele; however, its clinical significance for autosomal dominant cardiomyopathy is unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Uncertain
0.16
D
BayesDel_noAF
Pathogenic
0.60
CADD
Pathogenic
39
DANN
Uncertain
1.0
Eigen
Uncertain
0.64
Eigen_PC
Uncertain
0.48
FATHMM_MKL
Uncertain
0.77
D
Vest4
0.84
GERP RS
4.4
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.070
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.

Other links and lift over

dbSNP: rs730881068; hg19: chr19-55666189; COSMIC: COSV61276503; COSMIC: COSV61276503; API