ClinVar Genomic variation as it relates to human health

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, 37089884, 37652022, 25524337, 32746448, 33777698)

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. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. 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. ClinVar contains an entry for this variant (Variation ID: 177694). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 21839045, 22112859, 25524337, 27532257, 32746448, 33777698). This variant is not present in population databases (gnomAD no frequency). 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).

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.

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; 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). In a family described as having cases of severe heart failure with hypertrophic and restrictive features and cardiac conduction system disease, this variant was detected in an affected proband and two unaffected adult children (Arad M et al. Isr Med Assoc J, 2014 Nov;16:707-13). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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 cardiomypathy; however, its clinical significance for autosomal recessive dilated cardiomyopathy is unclear.