ClinVar Miner

Submissions for variant NM_000363.5(TNNI3):c.407G>A (p.Arg136Gln) (rs730881069)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Blueprint Genetics RCV000159213 SCV000928159 likely pathogenic not provided 2019-01-08 criteria provided, single submitter clinical testing
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000769526 SCV000900921 likely pathogenic Cardiomyopathy 2016-02-23 criteria provided, single submitter clinical testing
GeneDx RCV000159213 SCV000209159 uncertain significance not provided 2019-01-07 criteria provided, single submitter clinical testing The R136Q variant of uncertain significance in the TNNI3 gene has been previously reported in several probands with a clinical diagnosis of HCM (Millat et al., 2010; Coto et al., 2012; Teirlinck et al., 2012) as well as in multiple additional individuals referred for HCM genetic testing (Kapplinger et al., 2014; Walsh et al., 2017), although patient-specific clinical and segregation data were not provided. In addition, R136Q is not observed at a significant frequency in large population cohorts (Lek et al., 2016). Furthermore, R136Q is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. Nevertheless, in-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function.Therefore, R136Q in the TNNI3 gene is interpreted as a variant of uncertain significance.
Invitae RCV000167999 SCV000218650 likely pathogenic Hypertrophic cardiomyopathy 2018-12-02 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 136 of the TNNI3 protein (p.Arg136Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is not present in population databases (ExAC no frequency). This sequence change has been observed in individuals affected with hypertrophic cardiomyopathy (PMID: 20624503, 22765922, 27532257, 24510615, 28356264, Invitae). ClinVar contains an entry for this variant (Variation ID: 181576). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.

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