ClinVar Miner

Submissions for variant NM_000363.5(TNNI3):c.596G>A (p.Ser199Asn) (rs730881091)

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Total submissions: 3
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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 Familial hypertrophic cardiomyopathy 7 criteria provided, single submitter clinical testing
Invitae RCV001239093 SCV001411940 pathogenic Hypertrophic cardiomyopathy 2020-09-02 criteria provided, single submitter clinical testing This sequence change replaces serine with asparagine at codon 199 of the TNNI3 protein (p.Ser199Asn). The serine residue is highly conserved and there is a small physicochemical difference between serine and asparagine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) 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). 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: Possibly Damaging; Align-GVGD: Class C0). 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.

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