rs727504872

Positions:

• chr19-55156278-GC-G

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PVS1 PP5

The NM_000363.5(TNNI3):​c.204del​(p.Arg69AlafsTer8) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000168 in 1,610,834 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. R68R) has been classified as Benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000016 (0 hom.)
• Consequence: TNNI3 NM_000363.5 frameshift
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:8 U:5
• Conservation: PhyloP100: 0.100

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 19-55156278-GC-G is Pathogenic according to our data. Variant chr19-55156278-GC-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 179447.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=3, Uncertain_significance=5, Pathogenic=4}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TNNI3	NM_000363.5	c.204del	p.Arg69AlafsTer8	frameshift_variant	5/8	ENST00000344887.10	NP_000354.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TNNI3	ENST00000344887.10	c.204del	p.Arg69AlafsTer8	frameshift_variant	5/8	1	NM_000363.5	ENSP00000341838	P1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152126 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

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: 0.000479

GnomAD3 exomes AF: 0.0000381 AC: 9 AN: 236002 Hom.: 0 AF XY: 0.0000614 AC XY: 8 AN XY: 130196

Gnomad AFR exome AF: 0.0000758

Gnomad AMR exome AF: 0.000148

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000285

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000165 AC: 24 AN: 1458708 Hom.: 0 Cov.: 33 AF XY: 0.0000179 AC XY: 13 AN XY: 725612

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000112

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: 0.0000153

Gnomad4 OTH exome AF: 0.0000332

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152126 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74302

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000654

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: 0.000479

Alfa AF: 0.0000868 Hom.: 0

Bravo AF: 0.0000340

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:8 Uncertain:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:3 Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	Mar 24, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jan 11, 2023	Reported in association with cardiomyopathy or arrhythmia, without patient-specific clinical data (Chanavat et al. 2016); Frameshift 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; Reported in ClinVar with conflicting classifications and has been reported by a clinical laboratory in one homozygous individual with neonatal onset HCM/DCM (ClinVar Variant ID# 179447; SCV000205952.5); This variant is associated with the following publications: (PMID: 26688388, 31568572, 34213952, 35050212) -
Likely pathogenic, no assertion criteria provided	clinical testing	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Nov 13, 2013	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 -

Dilated cardiomyopathy 2A Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Hadassah Hebrew University Medical Center	Jun 20, 2019	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Breakthrough Genomics, Breakthrough Genomics	Aug 22, 2022	This variant has been reported in individuals affected with cardiomyopathies, arrhythmia syndromes, myocarditis [PMID: 26688388, 34213952] and also been reported in homozygous state in a pediatric patient affected with dilated cardiomyopathy [PMID: 31568572]. -

Cardiomyopathy Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	May 17, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	May 18, 2023	This variant deletes 1 nucleotide in exon 5 of the TNNI3 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. An experimental functional study using heart tissue from a homozygous individual affected with dilated cardiomyopathy has shown that TNNI3 protein was not expressed in heart tissue (PMID: 31568572). This variant has been reported in homozygosity in multiple individuals affected with early-onset dilated cardiomyopathy (PMID: 31568572, 35050212, 36981019); heterozygous carrier parents were either not clinically affected or were not fully clinically evaluated for TNNI3-related disorders. This variant has also been reported in heterozygosity in an individual affected with dilated cardiomyopathy (PMID: 36129056), in unclear zygosity in another individual affected with dilated cardiomyopathy (PMID: 34286374), and in an individual affected with cardiomyopathy or arrhythmia (PMID: 26688388). This variant has been identified in 9/236002 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. -

Primary familial dilated cardiomyopathy Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Aug 08, 2022

Variant summary: TNNI3 c.204delG (p.Arg69AlafsX8) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay. The variant allele was found at a frequency of 3.8e-05 in 236002 control chromosomes (gnomAD). c.204delG has been reported in the literature in multiple homozygous individuals affected with Dilated Cardiomyopathy who had inherited the variant from their unaffected heterozygous parents (e.g. Kuhnisch_2019, Pezzoli_2021, Seidel_2021). TNNI3 protein was absent and mRNA level was markedly reduced in heart biopsies from some of these homozygous patients (Kuhnisch_2019, Pezzoli_2021). Even though loss-of-function (LoF) has not been established as a molecular mechanism of disease for TNNI3 gene, accumulated evidence suggests that LoF variants can be causative for autosomal recessive Dilated Cardiomyopathy. These data indicate that the variant is likely to be associated with disease. Three ClinVar submitters (evaluation after 2014) cite the variant as pathogenic/likely pathogenic and four ClinVar submitters (evaluation after 2014) cite it as uncertain significance. Some submitters cite overlapping but not identical evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Primary dilated cardiomyopathy;C0027059:Myocarditis Pathogenic:1

Pathogenic, criteria provided, single submitter

research

Klaassen Lab, Charite University Medicine Berlin

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- -

Hypertrophic cardiomyopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 17, 2023

This sequence change creates a premature translational stop signal (p.Arg69Alafs*8) 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 (rs727504872, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with clinical features of autosomal recessive dilated cardiomyopathy (PMID: 31568572). ClinVar contains an entry for this variant (Variation ID: 179447). For these reasons, this variant has been classified as Pathogenic. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Aug 15, 2017

Variant classified as Uncertain Significance - Favor Pathogenic. The p.Arg69fs v ariant in TNNI3 has been observed in our laboratory in one homozygous individual with neonatal onset HCM/DCM. It has been identified in 5/33086 Latino chromosom es by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org/ ; dbSNP rs727504872). This variant has been reported in ClinVar variation ID 179 447. This frameshift variant is predicted to alter the protein?s amino acid sequ ence beginning at position 69 and lead to a premature termination codon 8 amino acids downstream. This alteration is then predicted to lead to a truncated or ab sent protein. Although this variant is predicted to be deleterious to the protei n, the variant spectrum of this gene has not been well characterized, and it rem ains unclear if these variant types play a role in disease. In summary, while th ere is some suspicion for a pathogenic role, the clinical significance of the p. Arg69fs variant is uncertain. -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 14, 2023

The c.204delG variant, located in coding exon 5 of the TNNI3 gene, results from a deletion of one nucleotide at nucleotide position 204, causing a translational frameshift with a predicted alternate stop codon (p.R69Afs*8). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. However, loss of function of TNNI3 has not been clearly established as a mechanism of disease. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

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

Other links and lift over

dbSNP: rs727504872; hg19: chr19-55667646;