Submissions for variant NM_000363.5(TNNI3):c.596G>A (p.Ser199Asn)

dbSNP: rs730881091

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000225742	SCV000209208	likely pathogenic	not provided	2018-03-21	criteria provided, single submitter	clinical testing	The S199N variant has been reported in multiple individuals with a diagnosis of HCM and was absent in at least 350 control chromosomes (Mogensen et al., 2004; Brito et al. 2005; Andersen et al. 2009; Brito et al., 2012). Mogensen et al. (2004) reported S199N in two unrelated families and this variant was found to segregate with disease in six family members, including two obligate carriers. The S199N variant was not observed in approximately 6100 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Additionally, the S199 residue was shown to be hyperphosphorylated in a canine heart failure model, and variants in the same residue (S199G) and in nearby residues (A197G, L198V, L198P, M201T, E202G, G203S, G203R) have been reported in HGMD in association with HCM (Zhang et al., 2012; Stenson et al., 2014), further supporting the functional importance of this residue and this region of the protein. Moreover, this substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Nevertheless, S199N is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded.
Laboratory of Genetics and Molecular Cardiology, University of São Paulo	RCV000201449	SCV000256203	uncertain significance	Hypertrophic cardiomyopathy 7		criteria provided, single submitter	clinical testing
Invitae	RCV001239093	SCV001411940	pathogenic	Hypertrophic cardiomyopathy	2023-10-14	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 199 of the TNNI3 protein (p.Ser199Asn). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 15607392, 16335287, 19035361, 27532257). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 181603). 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 disruptive. This variant disrupts the p.Ser199 amino acid residue in TNNI3. Other variant(s) that disrupt this residue have been observed in individuals with TNNI3-related conditions (PMID: 15607392), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV002354396	SCV002658618	likely pathogenic	Cardiovascular phenotype	2022-04-27	criteria provided, single submitter	clinical testing	The p.S199N variant (also known as c.596G>A), located in coding exon 8 of the TNNI3 gene, results from a G to A substitution at nucleotide position 596. The serine at codon 199 is replaced by asparagine, an amino acid with highly similar properties. This alteration has been reported in subjects with hypertrophic cardiomyopathy (HCM) and has been shown to segregate with disease (Mogensen J et al. J. Am. Coll. Cardiol., 2004 Dec;44:2315-25; Brito D et al. Rev Port Cardiol, 2005 Sep;24:1137-46; Andersen PS et al. Hum. Mutat., 2009 Mar;30:363-70; Walsh R et al. Genet. Med., 2017 02;19:192-203). This variant was also reported in a dilated cardiomyopathy cohort with no clinical details provided (Mazzarotto F et al. Circulation, 2020 02;141:387-398). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.