Submissions for variant NM_000363.5(TNNI3):c.592C>G (p.Leu198Val)

gnomAD frequency: 0.00001  dbSNP: rs727504285

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000628864	SCV000203953	likely pathogenic	Hypertrophic cardiomyopathy	2021-09-07	criteria provided, single submitter	clinical testing	The p.Leu198Val variant in TNNI3 has been reported in at least 11 individuals with hypertrophic cardiomyopathy (HCM) and segregated with HCM in 5 affected relatives from 4 families (Maron 2012 PMID: 21839045, Otsuka 2012 PMID: 22112859, Arad 2014 PMID: 25558701, Coppini 2014 PMID: 25524337, Lopes 2013 PMID: 23396983, LMM data, Invitae pers. comm, GeneDx pers. comm.). Some adult relatives of two of these individuals who were heterozygous carriers of this variant were not reported to have HCM, suggesting reduced penetrance (CHEO pers. comm., Invitae pers. comm.). Additionally, this variant has also been identified in a teenager with dilated cardiomyopathy (DCM; no other variants identified at the time of testing) and segregated with disease in 2 affected relatives (1 with HCM and 1 with DCM). It has also been identified in 0.01% (1/10072) of Ashkenazi Jewish chromosomes by gnomAD but was absent from all other populations (http://gnomad.broadinstitute.org). Splice prediction tools suggest the creation of a cryptic 5' splice site; however, this information is not predictive enough to determine pathogenicity. Additional computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant HCM, with possibly reduced penetrance. ACMG/AMP Criteria applied: PS4, PP1_Moderate, PM2_Supporting.
GeneDx	RCV000518842	SCV000209193	likely pathogenic	not provided	2024-12-13	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 19914256, 26526134, 19754353, 21839045, 25558701, 23861362, 25351510, 22112859, 28087566, 19033660, 27532257, 25524337, 32746448, 33777698, 37652022, 37089884)
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV000623545	SCV000740430	likely pathogenic	Primary familial hypertrophic cardiomyopathy	2017-07-12	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000628864	SCV000749772	pathogenic	Hypertrophic cardiomyopathy	2024-12-15	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 198 of the TNNI3 protein (p.Leu198Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 21839045, 22112859, 25524337, 27532257, 32746448, 33777698, 37089884). ClinVar contains an entry for this variant (Variation ID: 177694). 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 tolerated. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. This variant disrupts the p.Leu198 amino acid residue in TNNI3. Other variant(s) that disrupt this residue have been observed in individuals with TNNI3-related conditions (PMID: 15698845), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV002354364	SCV002647510	likely pathogenic	Cardiovascular phenotype	2024-12-06	criteria provided, single submitter	clinical testing	The p.L198V variant (also known as c.592C>G), located in coding exon 8 of the TNNI3 gene, results from a C to G substitution at nucleotide position 592. The leucine at codon 198 is replaced by valine, an amino acid with highly similar properties. This variant has been detected in several individuals diagnosed with hypertrophic cardiomyopathy (HCM) and in individuals from HCM cohorts or cohorts referred for HCM genetic testing (Lopes LR et al. Heart, 2015 Feb;101:294-301; Maron BJ et al. Heart Rhythm, 2012 Jan;9:57-63; Otsuka H et al. Circ J, 2012 Nov;76:453-61; Arad M et al. Isr Med Assoc J, 2014 Nov;16:707-13; Coppini R et al. J Am Coll Cardiol, 2014 Dec;64:2589-2600; Walsh R et al. Genet Med, 2017 02;19:192-203; Burstein DS et al. Pediatr Res, 2021 05;89:1470-1476; external communication). This variant has also been reported to segregate with HCM in families (Cava F et al. Mol Genet Metab Rep, 2021 Jun;27:100743; external communication). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the supporting evidence, this variant is expected to be causative of autosomal dominant cardiomyopathy; however, its clinical significance for autosomal recessive dilated cardiomyopathy is unclear.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003486687	SCV004239773	likely pathogenic	Cardiomyopathy	2023-05-12	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV004786410	SCV005399514	likely pathogenic	Hypertrophic cardiomyopathy 7	2022-02-02	criteria provided, single submitter	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) (PMIDs: 19914256, 21533915). (I) 0108 - This gene is associated with both recessive and dominant disease. The recessive form of inheritance is the exception and has only been reported in a small number of families (PMIDs: 15070570, 23270746). (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 leucine to valine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2) <0.001 for a dominant condition (1 heterozygote, 0 homozygotes). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported in multiple individuals with HCM (PMID: 27532257, 22112859, 28087566, ClinVar). This variant has also been identified in HCM probands with additional variants in other genes (PMID: 33777698, 25558701, 21839045, 23396983). (SP) 0906 - Segregation evidence for this variant is inconclusive. This variant segregated with HCM in two affected siblings of a HCM proband (PMID: 22112859). This variant has also been identified in two unaffected daughters of a HCM proband, however, this could be due to incomplete or age-related penetrance (PMID: 25558701). (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Color Diagnostics, LLC DBA Color Health	RCV003486687	SCV006061218	likely pathogenic	Cardiomyopathy	2024-01-10	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with valine at codon 198 in the C-terminal mobile domain of the TNNI3 protein. Computational prediction tools indicate that this variant has a neutral impact on protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in over 15 individuals affected with hypertrophic cardiomyopathy (PMID: 21839045, 22112859, 25351510, 25524337, 25558701, 25611685, 27532257, 29710196, 29875424, 30297972, 32481709, 32746448, 33777698, 33495597, 34556856, 37089884; communication with an external laboratory, ClinVar SCV000209193.8), and in one individual affected with restrictive cardiomyopathy (PMID: 28087566). It has been shown that this variant segregates with disease in 7 affected individuals across 3 families (PMID: 33777698; communication with an external laboratory, ClinVar SCV000209193.8). In one individual affected with both hypertrophic cardiomyopathy and long QT syndrome, this variant co-occurred a pathogenic variant in the KCNQ1 gene. This TNNI3 variant segregated with hypertrophic cardiomyopathy in one parent, while the KCNQ1 variant segregated with long QT syndrome in the other parent (PMID: 33777698). This variant has been identified in 1/249572 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.