Submissions for variant NM_000363.5(TNNI3):c.539A>G (p.Asp180Gly)

dbSNP: rs1060499912

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000454790	SCV000540563	uncertain significance	not specified	2016-08-12	criteria provided, single submitter	clinical testing	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Reported in 2 DCM and 1 LVNC probands, ClinVar: LP by GeneDx
Ambry Genetics	RCV000621120	SCV000736607	uncertain significance	Cardiovascular phenotype	2019-09-25	criteria provided, single submitter	clinical testing	The p.D180G variant (also known as c.539A>G), located in coding exon 7 of the TNNI3 gene, results from an A to G substitution at nucleotide position 539. The aspartic acid at codon 180 is replaced by glycine, an amino acid with some similar properties. This variant has been reported in subjects with dilated cardiomyopathy (DCM) and left ventricular non-compaction (LVNC) (Hershberger RE, Circ Cardiovasc Genet 2010 Apr; 3(2):155-61; Hoedemaekers YM, Circ Cardiovasc Genet 2010 Jun; 3(3):232-9; Rampersaud E, Prog. Pediatr. Cardiol. 2011 Jan; 31(1):39-47). This variant was identified in one individual with DCM, but was not seen in the mother who also had features of DCM (Mook OR, J. Med. Genet. 2013 Sep; 50(9):614-26). This variant was also identified in a subject with LVNC, but was not seen in a maternal aunt who also had features of LVNC (Hoedemaekers YM, Circ Cardiovasc Genet 2010 Jun; 3(3):232-9). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on available evidence to date, the clinical significance of this variant remains unclear.
Invitae	RCV000628888	SCV000749796	uncertain significance	Hypertrophic cardiomyopathy	2023-10-13	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 180 of the TNNI3 protein (p.Asp180Gly). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with TNNI3-related conditions (PMID: 20215591, 21483645, 21533915, 23785128, 30847666, 31112419, 31737537). ClinVar contains an entry for this variant (Variation ID: 403557). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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.
GeneDx	RCV001528409	SCV001815004	uncertain significance	not provided	2019-10-24	criteria provided, single submitter	clinical testing	Identified in patients with dilated cardiomyopathy referred for genetic testing at GeneDx and in published literature (Hershberger et al., 2010; Hoedemaekers et al., 2010; Rampersaud et al., 2011; Mook et al., 2013; Te Rijdt et al., 2019); also reported in one three month old infant with left ventricular non-compaction (van den Wijngaard et al., 2011); Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 403557; Landrum et al., 2016); Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 30847666, 31737537, 31112419, 21483645, 20530761, 23785128, 20215591, 21533915)
Color Diagnostics, LLC DBA Color Health	RCV003532121	SCV004359896	uncertain significance	Cardiomyopathy	2023-04-19	criteria provided, single submitter	clinical testing	This missense variant replaces aspartic acid with glycine at codon 180 of the TNNI3 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with dilated cardiomyopathy (PMID: 20215591, 21483645, 23785128, 25163546, 30847666, 31112419, 31737537). It has also been reported in an individual affected with left ventricular noncompaction (PMID: 20530761, 21533915, 31771441) and in an individual affected with noncompaction cardiomyopathy (PMID: 29447731). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV001528409	SCV001740122	uncertain significance	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV001528409	SCV001928572	uncertain significance	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001528409	SCV001979368	uncertain significance	not provided		no assertion criteria provided	clinical testing