rs397516359

Variant names:

• chr19-55157585-G-A
• rs397516359
• NM_000363.5:c.5C>T

Your query was ambiguous. Multiple possible variants found:

• chr19-55157585-G-A
• chr19-55157585-G-C
• chr19-55157585-G-T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PP3 PP5

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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A2P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000021 (0 hom.)
• Consequence: TNNI3 NM_000363.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4 U:8
• Conservation: PhyloP100: 1.86
• Publications: 4 publications found

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 Gene-Disease associations (from GenCC):

• hypertrophic cardiomyopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• dilated cardiomyopathy 2A

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• hypertrophic cardiomyopathy 7

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), G2P
• cardiomyopathy, familial restrictive, 1

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• dilated cardiomyopathy 1FF

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• dilated cardiomyopathy

  Inheritance: AD Classification: MODERATE Submitted by: ClinGen
• familial isolated dilated cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• familial isolated restrictive cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• arrhythmogenic right ventricular cardiomyopathy

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ENSG00000267110 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• 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 VariationId is 43397.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNNI3	NM_000363.5	c.5C>T	p.Ala2Val	missense_variant	Exon 1 of 8	ENST00000344887.10	NP_000354.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TNNI3	ENST00000344887.10	c.5C>T	p.Ala2Val	missense_variant	Exon 1 of 8	1	NM_000363.5	ENSP00000341838.5
ENSG00000267110	ENST00000587871.1	n.*108C>T		non_coding_transcript_exon_variant	Exon 5 of 9	5		ENSP00000473050.1
ENSG00000267110	ENST00000587871.1	n.*108C>T		3_prime_UTR_variant	Exon 5 of 9	5		ENSP00000473050.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152136 Hom.: 0 Cov.: 32

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

GnomAD2 exomes AF: 0.0000321 AC: 8 AN: 248866 AF XY: 0.0000296

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000205 AC: 30 AN: 1461742 Hom.: 0 Cov.: 32 AF XY: 0.0000289 AC XY: 21 AN XY: 727184

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26122

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000243 AC: 21 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53396

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00000630 AC: 7 AN: 1111930

Other (OTH) AF: 0.0000331 AC: 2 AN: 60388

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152136 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74312

African (AFR) AF: 0.00 AC: 0 AN: 41438

American (AMR) AF: 0.00 AC: 0 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68012

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.0000260 Hom.: 0

ExAC AF: 0.0000331 AC: 4

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4 Uncertain:8

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Dilated cardiomyopathy 2A Pathogenic:2

Feb 02, 2022

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Aug 14, 2009

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Hypertrophic cardiomyopathy 7 Pathogenic:1 Uncertain:1

Sep 22, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Feb 01, 2024

Neuberg Centre For Genomic Medicine, NCGM

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The observed has been reported previously in homozygous state in individual(s) affected with TNNI3 related disorders (Sorrentino et al., 2023; Murphy et al., 2004). It has also been observed to segregate with disease in related individuals. Functional studies have demonstrated conflicting results regarding the impact on ATPase regulation and troponin function (Murphy et al., 2004).

Hypertrophic cardiomyopathy Pathogenic:1 Uncertain:1

Jul 19, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Jul 10, 2024

All of Us Research Program, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Cardiomyopathy Uncertain:2

Dec 20, 2019

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jun 09, 2024

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces alanine with valine at codon 2 of the TNNI3 protein. Computational prediction tools indicate that this variant's impact on protein structure and function is inconclusive. 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

Sep 11, 2025

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis suggests that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 19590045, 31568572, 15070570, 31534214, 32870709, 32746448, 36252119, 22940544)

Jul 28, 2021

AiLife Diagnostics, AiLife Diagnostics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not specified Uncertain:1

Jun 28, 2019

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Cardiovascular phenotype Uncertain:1

Dec 04, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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	D
BayesDel_noAF	Pathogenic	0.23
CADD	Benign	23
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.49	T
Eigen	Benign	0.15
Eigen_PC	Benign	0.092
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.31	T
M_CAP	Uncertain	0.28	D
MetaRNN	Pathogenic	0.78	D
MetaSVM	Uncertain	0.41	D
MutationAssessor	Benign	0.69	N
PhyloP100		1.9
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-0.030	N
REVEL	Uncertain	0.61
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Vest4		0.50
ClinPred		0.29	T
GERP RS		2.8
PromoterAI		-0.20	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.20
Mutation Taster		=78/22	polymorphism

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

Other links and lift over

dbSNP: rs397516359; hg19: chr19-55668953; COSMIC: COSV100787932; COSMIC: COSV100787932;