rs397516359

Positions:

chr19-55157585-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1PP3PP5

The NM_000363.5(TNNI3):c.5C>T(p.Ala2Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000192 in 1,613,878 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).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000021 ( 0 hom. )

Consequence

TNNI3
NM_000363.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3U:8

Conservation

PhyloP100: 1.86

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:

ENSG00000267110 (HGNC:):

ENSG00000267110 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM1

In a modified_residue N-acetylalanine (size 0) in uniprot entity TNNI3_HUMAN

PP3

MetaRNN computational evidence supports a deleterious effect, 0.784

PP5

Variant 19-55157585-G-A is Pathogenic according to our data. Variant chr19-55157585-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 43397.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=7, Likely_pathogenic=2}. Variant chr19-55157585-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TNNI3	NM_000363.5 linkuse as main transcript	c.5C>T	p.Ala2Val	missense_variant	1/8	ENST00000344887.10	NP_000354.4	P19429Q6FGX2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
TNNI3	ENST00000344887.10 linkuse as main transcript	c.5C>T	p.Ala2Val	missense_variant	1/8	1	NM_000363.5	ENSP00000341838.5	P19429
ENSG00000267110	ENST00000587871.1 linkuse as main transcript	n.*108C>T		non_coding_transcript_exon_variant	5/9	5		ENSP00000473050.1	M0R381
ENSG00000267110	ENST00000587871.1 linkuse as main transcript	n.*108C>T		3_prime_UTR_variant	5/9	5		ENSP00000473050.1	M0R381

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152136

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:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000321

AC:

AN:

248866

Hom.:

AF XY:

0.0000296

AC XY:

AN XY:

135106

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000262

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000205

AC:

AN:

1461742

Hom.:

Cov.:

AF XY:

0.0000289

AC XY:

AN XY:

727184

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:

0.000243

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000630

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152136

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74312

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:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000260

Hom.:

ExAC

AF:

0.0000331

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3Uncertain:8

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Dilated cardiomyopathy 2A

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Feb 02, 2022	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as likely pathogenic. Following criteria are met: 0103 - Gain of function and loss of function are reported mechanisms of disease in this gene. The former is associated with familial restrictive cardiomyopathy 1 (MIM#115210) and hypertrophic cardiomyopathy 7 (MIM#613690), while the latter is associated with dilated cardiomyopathy 1FF (MIM#613286) (PMID: 19914256, 21533915). (I) 0108 - This gene is associated with both recessive and dominant disease. Although predominantly associated with autosomal dominant disease, there are emerging reports of autosomal recessive cardiomyopathy (PMID: 15070570, 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) 0200 - Variant is predicted to result in a missense amino acid change from alanine to valine. (I) 0252 - This variant is homozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.001 (8 heterozygotes, 0 homozygotes). (SP) 0503 - Missense variant consistently predicted to be tolerated by multiple in silico tools or not conserved in placental mammals with a minor amino acid change. (SB) 0600 - Variant is located in the annotated Troponin I N-extension domain (Pfam). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0803 - This variant has limited previous evidence of pathogenicity in unrelated individuals. This variant has been described in a DCM family with two homozygous affected siblings, where the heterozygous third sibling and parents were unaffected (PMID: 15070570). This variant was also reported in a young woman with DCM, although the zygosity was not stated (PMID: 31534214). ClinVar has 4 VUS entries for this variant by clinical testing; at least one of these was identified in the homozygous state in an individual with DCM (personal correspondence). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. In vitro studies indicate that this variant results in reduced binding to cTnT and altered myofilament activation, although the relevance of this evidence to disease pathology is unknown (PMID: 15070570, 22940544). (SP) 1209 - This variant has been shown to be both maternally and paternally inherited (biallelic) (LABID). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 14, 2009	- -

Hypertrophic cardiomyopathy

Pathogenic:1Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Jul 10, 2024	This missense variant replaces alanine with valine at codon 2 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 disrupts the interaction between troponin I and troponin T (PMID: 15070570), and affects myofilament function (PMID: 22940544). This variant has been reported in homozygous state in two siblings affected with dilated cardiomyopathy (PMID: 15070570); their parents and another sibling were all healthy heterozygous carriers. This variant has also been reported in homozygous state in an individual affected with childhood-onset dilated cardiomyopathy (PMID: 32870709) and in unspecified zygosity in another individual affected with childhood-onset dilated cardiomyopathy (PMID: 32746448). This variant has also been identified in 8/248866 chromosomes in the general population by the Genome Aggregation Database (gnomAD). 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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 22, 2024	This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 2 of the TNNI3 protein (p.Ala2Val). This variant is present in population databases (rs397516359, gnomAD 0.03%). This missense change has been observed in individuals with autosomal recessive dilated cardiomyopathy (PMID: 32870709; Invitae). ClinVar contains an entry for this variant (Variation ID: 43397). 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: 15070570, 22940544). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Cardiomyopathy

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Dec 20, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jun 08, 2023	This missense variant replaces alanine with valine at codon 2 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 disrupts the interaction between troponin I and troponin T (PMID: 15070570), and affects myofilament function (PMID: 22940544). This variant has been reported in homozygous state in two siblings affected with dilated cardiomyopathy (PMID: 15070570); their parents and another sibling were all healthy heterozygous carriers. This variant has also been reported in homozygous state in an individual affected with childhood-onset dilated cardiomyopathy (PMID: 32870709) and in unspecified zygosity in another individual affected with childhood-onset dilated cardiomyopathy (PMID: 32746448). This variant has also been identified in 8/248866 chromosomes in the general population by the Genome Aggregation Database (gnomAD). 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. -

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	Jul 28, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Nov 19, 2019	Reported as a homozygous variant in two siblings with DCM; both heterozygous parents and one heterozygous sibling were reported to have a normal cardiac work-up (Murphy et al., 2004); Functional studies have demonstrated conflicting results regarding the impact on ATPase regulation and troponin function (Murphy et al., 2004; Carballo et al., 2009; Henze et al., 2013); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 43397; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 19590045, 31568572, 22940544, 15070570, 31534214, 32870709) -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jun 28, 2019

The p.Ala2Val variant in TNNI3 has been reported as homozygous in 2 individuals with DCM and segregated in the homozygous state in 1 affected sibling (Murphy 2004, LMM data). In vitro functional studies provide some evidence that the p.Ala2Val variant may impact protein function (Murphy 2004, Henze 2013). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses suggest that this variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. This variant has been identified in 0.03% (8/30592) of South Asian chromosomes by gnomAD (http://gnomad.broadinstitute.org). This frequency raises the possibility that the variant does not cause disease in the heterozygous state but is not inconsistent with a recessive mode of inheritance. In summary, due to conflicting evidence, the clinical significance of the p.Ala2Val variant is uncertain. ACMG/AMP Criteria applied: PP1, PM3_Supporting, PS3_Supporing, BS1_Supporting, BP4. -

Hypertrophic cardiomyopathy 7

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center

Sep 22, 2024

- -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 04, 2024

The p.A2V variant (also known as c.5C>T), located in coding exon 1 of the TNNI3 gene, results from a C to T substitution at nucleotide position 5. The alanine at codon 2 is replaced by valine, an amino acid with similar properties. This variant has been identified in the homozygous state and/or in conjunction with other TNNI3 variant(s) in individual(s) with features consistent withTNNI3-related dilated cardiomyopathy; however, heterozygotes have been reported as unaffected (Murphy RT et al. Lancet, 2004 Jan;363:371-2; Al-Hassnan ZN et al. Circ Genom Precis Med, 2020 Oct;13:504-514; Bagnall RD et al. Circ Genom Precis Med, 2022 Dec;15:e003686). Functional studies suggest this variant may impact protein function; however, additional evidence is needed to confirm these findings (Murphy RT et al. Lancet, 2004 Jan;363:371-2; Carballo S et al. Circ Res, 2009 Aug;105:375-82; Henze M et al. Biochim Biophys Acta. 2013 Apr;1833(4):823-32). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on data from gnomAD, the frequency for this variant is above the maximum credible frequency for an autosomal dominant disease-causing variant in this gene based on internally established thresholds (Karczewski et al. Nature. 2020 May;581(7809):434-443; Whiffin et al. Genet Med. 2017 10;19:1151-1158). Based on the available evidence, the clinical significance of this variant remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

CardioboostCm

Benign

0.066

BayesDel_addAF

Uncertain

0.12

BayesDel_noAF

Pathogenic

0.23

CADD

Benign

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.49

Eigen

Benign

0.15

Eigen_PC

Benign

0.092

FATHMM_MKL

Uncertain

0.85

LIST_S2

Benign

0.31

M_CAP

Uncertain

0.28

MetaRNN

Pathogenic

0.78

MetaSVM

Uncertain

0.41

MutationAssessor

Benign

0.69

PrimateAI

Uncertain

0.77

PROVEAN

Benign

-0.030

REVEL

Uncertain

0.61

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.50

MutPred

0.70

Loss of glycosylation at S6 (P = 0.1676);

MVP

0.94

MPC

1.1

ClinPred

0.29

GERP RS

2.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

Varity_R

0.20

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