rs727503507

Positions:

• chr19-55156224-CG-C

Variant summary

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

The NM_000363.5(TNNI3):​c.258delC​(p.Leu88fs) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000089 in 1,460,484 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000089 (0 hom.)
• Consequence: TNNI3 NM_000363.5 frameshift
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:4
• Conservation: PhyloP100: -0.352

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]

ENSG00000267110 (HGNC:):

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 19-55156224-CG-C is Pathogenic according to our data. Variant chr19-55156224-CG-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 165522.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=4, Pathogenic=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TNNI3	NM_000363.5	c.258delC	p.Leu88fs	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.258delC	p.Leu88fs	frameshift_variant	5/8	1	NM_000363.5	ENSP00000341838.5
ENSG00000267110	ENST00000587871.1	n.*360delC		non_coding_transcript_exon_variant	8/9	5		ENSP00000473050.1
ENSG00000267110	ENST00000587871.1	n.*360delC		3_prime_UTR_variant	8/9	5		ENSP00000473050.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000825 AC: 2 AN: 242566 Hom.: 0 AF XY: 0.0000150 AC XY: 2 AN XY: 133250

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000291

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: 0.00000922

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000890 AC: 13 AN: 1460484 Hom.: 0 Cov.: 32 AF XY: 0.00000551 AC XY: 4 AN XY: 726588

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

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: 0.0000108

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hypertrophic cardiomyopathy Pathogenic:1 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Aug 06, 2024	This variant (also known as A86fs in literature due to the use of alternate nomenclature) 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. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in two individuals affected with hypertrophic cardiomyopathy (PMID: 18533079, 25524337). This variant has also been observed in homozygous state in a child affected with left ventricular non-compaction and dilated cardiomyopathy, whose heterozygous consanguineous parents were reported to be healthy (PMID: 34036930). This variant has been identified in 2/242566 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Clinical relevance of loss-of-function truncation and splice variants in the TNNI3 gene 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 04, 2024	This sequence change creates a premature translational stop signal (p.Leu88Trpfs*27) 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 (rs727503507, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with autosomal recessive TNNI3-related conditions (PMID: 34036930). This variant is also known as delC (p.A86fs). ClinVar contains an entry for this variant (Variation ID: 165522). For these reasons, this variant has been classified as Pathogenic. -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 30, 2022	The p.Leu88TrpfsX27 variant in TNNI3 has been reported in 2 individuals with HCM, 1 of whom also carried a suspicious variant in MYH7 (Olivotto 2008). It was also identified in 2/242566 chromosomes by gnomAD (https://gnomad.broadinstitute.org). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 88 and leads to a premature termination codon 27 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. While heterozygous loss-of-function variants in TNNI3 are uncommon, they have been reported in cases of HCM (Olivotto 2008) and RCM with functional evidence of calcium sensitization (Kaski 2008, Kostareva 2009). However, it remains unclear if the p.Leu88TrpfsX27 variant would impact protein function. In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PVS1_Moderate, PM2. -

Hypertrophic cardiomyopathy 7 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Nov 03, 2018

This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -

Cardiomyopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Mar 15, 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. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in two individuals affected with hypertrophic cardiomyopathy (PMID: 18533079, 25524337). This variant has also been observed in homozygous state in a child affected with left ventricular non-compaction and dilated cardiomyopathy, whose heterozygous consanguineous parents were reported to be healthy (PMID: 34036930). This variant has been identified in 2/242566 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Clinical relevance of loss-of-function truncation and splice variants in the TNNI3 gene 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. -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 30, 2022

The c.258delC variant, located in coding exon 5 of the TNNI3 gene, results from a deletion of one nucleotide at nucleotide position 258, causing a translational frameshift with a predicted alternate stop codon (p.L88Wfs*27). This alteration, which is also known as delC A86fs, has been reported in hypertrophic cardiomyopathy cohorts and a pediatric cardiomyopathy cohort; however, clinical details were limited in some cases (Olivotto I et al. Mayo Clin Proc, 2008 Jun;83:630-8; Coppini R et al. J Am Coll Cardiol, 2014 Dec;64:2589-2600; Mehaney DA et al. Cardiol Young, 2022 Feb;32:295-300). Truncating alterations in TNNI3 have been reported in patients with restrictive cardiomyopathy (RCM) and hypertrophic cardiomyopathy (HCM) (Kaski JP et al. Heart. 2008;94(11):1478-84; Kostareva A et al. Int J Cardiol. 2009;131(3):410-2; Olivotto I et al. J Am Coll Cardiol. 2011;58(8):839-48; van den Wijngaard A et al. Neth Heart J. 2011;19(7-8):344-51). 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)		0.010		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: rs727503507; hg19: chr19-55667592;