rs727503507
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PVS1PP5
The NM_000363.5(TNNI3):c.258del(p.Leu88TrpfsTer27) 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). Synonymous variant affecting the same amino acid position (i.e. A86A) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_000363.5 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 9 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TNNI3 | NM_000363.5 | c.258del | p.Leu88TrpfsTer27 | frameshift_variant | 5/8 | ENST00000344887.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TNNI3 | ENST00000344887.10 | c.258del | p.Leu88TrpfsTer27 | frameshift_variant | 5/8 | 1 | NM_000363.5 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 exomes AF: 0.00000825 AC: 2AN: 242566Hom.: 0 AF XY: 0.0000150 AC XY: 2AN XY: 133250
GnomAD4 exome AF: 0.00000890 AC: 13AN: 1460484Hom.: 0 Cov.: 32 AF XY: 0.00000551 AC XY: 4AN XY: 726588
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Hypertrophic cardiomyopathy Pathogenic:1Uncertain:2
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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Apr 03, 2023 | 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 | Invitae | 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. - |
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:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at