ClinVar Miner

Submissions for variant NM_000363.5(TNNI3):c.577A>G (p.Lys193Glu) (rs730881080)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000159243 SCV000209189 uncertain significance not provided 2015-07-30 criteria provided, single submitter clinical testing The K193E variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The K193E 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. The K193E variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. Missense mutations in nearby residues (R192C, R192H, I195M, D196N) have been reported in the Human Gene Mutation Database in association with cardiomyopathy (Stenson et al., 2014), supporting the functional importance of this region of the protein. Nevertheless, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant.
Invitae RCV001296186 SCV001485142 uncertain significance Hypertrophic cardiomyopathy 2020-08-27 criteria provided, single submitter clinical testing This sequence change replaces lysine with glutamic acid at codon 193 of the TNNI3 protein (p.Lys193Glu). The lysine residue is highly conserved and there is a small physicochemical difference between lysine and glutamic acid. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with TNNI3-related conditions. ClinVar contains an entry for this variant (Variation ID: 181590). 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: Probably Damaging; Align-GVGD: Class C0). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Institute of Human Genetics,University of Wuerzburg RCV001296186 SCV001519638 likely pathogenic Hypertrophic cardiomyopathy no assertion criteria provided clinical testing

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