Submissions for variant NM_000363.5(TNNI3):c.626A>C (p.Glu209Ala)

dbSNP: rs730881083

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000505779	SCV000209199	uncertain significance	not provided	2017-03-07	criteria provided, single submitter	clinical testing	A variant of uncertain significance has been identified in the TNNI3 gene. The E209A variant has been reported as a possibly deleterious variant in at least 5 unrelated probands with cardiomyopathy (van den Wijngaard et al., 2011); however, familial segregation information and in vitro functional studies were not included. Nevertheless, the E209A variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). This 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. Additionally, this substitution occurs at a position that is conserved in mammals. Finally, in silico analysis predicts this variant is probably damaging to the protein structure/function.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000809873	SCV000950054	uncertain significance	Hypertrophic cardiomyopathy	2021-02-16	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"). This variant has been observed in several individuals affected with hypertrophic cardiomyopathy and in one individual with a combination of hypertrophic and restrictive cardiomyopathy (PMID: 21533915, 27532257). ClinVar contains an entry for this variant (Variation ID: 181595). This variant is not present in population databases (ExAC no frequency). This sequence change replaces glutamic acid with alanine at codon 209 of the TNNI3 protein (p.Glu209Ala). The glutamic acid residue is highly conserved and there is a moderate physicochemical difference between glutamic acid and alanine.
Ambry Genetics	RCV002354395	SCV002655874	uncertain significance	Cardiovascular phenotype	2022-05-29	criteria provided, single submitter	clinical testing	The p.E209A variant (also known as c.626A>C), located in coding exon 8 of the TNNI3 gene, results from an A to C substitution at nucleotide position 626. The glutamic acid at codon 209 is replaced by alanine, an amino acid with dissimilar properties. This alteration has been reported in a subject with features of restrictive cardiomyopathy and hypertrophic cardiomyopathy (HCM) cohorts (van den Wijngaard A et al. Neth Heart J, 2011 Aug;19:344-51; Walsh R et al. Genet Med, 2017 02;19:192-203; Marschall C et al. Cardiovasc Diagn Ther, 2019 Oct;9:S292-S298; van Lint FHM et al. Neth Heart J, 2019 Jun;27:304-309). 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.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000505779	SCV001743879	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000505779	SCV001918321	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000505779	SCV001958982	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000505779	SCV001972170	pathogenic	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000505779	SCV001977947	pathogenic	not provided		no assertion criteria provided	clinical testing