rs727503499
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PM5PP3_ModeratePP5_Very_Strong
The NM_000363.5(TNNI3):c.574C>T(p.Arg192Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R192L) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000363.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TNNI3 | NM_000363.5 | c.574C>T | p.Arg192Cys | missense_variant | 8/8 | ENST00000344887.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TNNI3 | ENST00000344887.10 | c.574C>T | p.Arg192Cys | missense_variant | 8/8 | 1 | NM_000363.5 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome Cov.: 31
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Oct 27, 2022 | Reported in additional unrelated patients with HCM or RCM in published literature (Millat et al., 2010; van den Wijngaard et al., 2011); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 21533915, 31064352, 35061126, 33429969, 33841591, 35345275, 34930847, 29907873, 20800588, 31568572, 31995186) - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jun 01, 2018 | - - |
Restrictive cardiomyopathy Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Feb 09, 2018 | The p.Arg192Cys variant in TNNI3 has been reported in 1 individual with HCM and 1 child with RCM (Millat 2010, van den Wijngaard 2011). In addition, the p.Arg19 2Cys variant has been identified by our laboratory in 3 children with RCM and 1 child with RCM and HCM, and identified as an apparently de novo occurrence in 3 of these cases. It was absent from large population studies. Computational predi ction tools and conservation analysis suggest that this variant may impact the p rotein, though this information is not predictive enough to determine pathogenic ity. Furthermore, three different pathogenic or likely pathogenic variants at th is position, (p.Arg192His, p.Arg192Pro, and p.Arg192Leu) have been identified in multiple individuals with HCM and/or RCM and have occurred de novo in multiple cases, strongly supporting that changes at this position may lead to disease. In summary, this variant meets criteria to be classified as pathogenic for RCM in an autosomal dominant manner based on the presence of this variant in affected i ndividuals with multiple de novo occurrences, absence from controls, and presenc e of other pathogenic variants involving this codon. ACMG/AMP Criteria applied: PM6_Strong, PM2, PS4_Moderate, PM5, PP3. - |
Hypertrophic cardiomyopathy 7 Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | Clinical Laboratory Sciences Program (CLSP), King Saud bin Abdulaziz University for Health Sciences (KSAU-HS) | Apr 01, 2023 | - - |
Hypertrophic cardiomyopathy 7;C1861861:Cardiomyopathy, familial restrictive, 1;C2678474:Dilated cardiomyopathy 2A;C2750091:Dilated cardiomyopathy 1FF Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago | Mar 30, 2021 | TNNI3 NM_000363.4 exon 8 p.Arg192Cys (c.574C>T): This variant has been reported in the literature in 1 individual with restrictive cardiomyopathy (Van de Wijngaard 2011 PMID:21533915) and has been identified by our laboratory as de novo in 1 individual with sudden unexplained death. This variant is not present in large control databases. This variant is present in ClinVar (Variation ID:165510). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. Of note, other variants at this same codon have strong evidence for pathogenicity (p.Arg192His) and/or have been reported in the literature in individuals with disease (p.Arg192Leu), supporting that this region has significance. In summary, data on this variant is highly suspicious for disease, but requires further evidence for pathogenicity. Therefore, this variant classified as likely pathogenic. - |
Hypertrophic cardiomyopathy Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Mar 09, 2022 | For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg192 amino acid residue in TNNI3. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12531876, 25611685). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 165510). This missense change has been observed in individual(s) with clinical features of TNNI3-related conditions (PMID: 20800588, 21533915, 29907873; Invitae). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 192 of the TNNI3 protein (p.Arg192Cys). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at