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

dbSNP: rs730881080

Total submissions: 4

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	2022-01-14	criteria provided, single submitter	clinical testing	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. 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"). ClinVar contains an entry for this variant (Variation ID: 181590). This variant has not been reported in the literature in individuals affected with TNNI3-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 193 of the TNNI3 protein (p.Lys193Glu).
Ambry Genetics	RCV002354394	SCV002653105	uncertain significance	Cardiovascular phenotype	2016-07-14	criteria provided, single submitter	clinical testing	The p.K193E variant (also known as c.577A>G), located in coding exon 8 of the TNNI3 gene, results from an A to G substitution at nucleotide position 577. The lysine at codon 193 is replaced by glutamic acid, an amino acid with similar properties. This variant was previously reported in the SNPDatabase as rs730881080. This variant was not reported in population based cohorts in the following databases: NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6130 samples (12260 alleles) with coverage at this position. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Institute of Human Genetics, University of Wuerzburg	RCV001296186	SCV001519638	likely pathogenic	Hypertrophic cardiomyopathy		no assertion criteria provided	clinical testing