ClinVar Miner

Submissions for variant NM_000363.5(TNNI3):c.539A>G (p.Asp180Gly) (rs1060499912)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare 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 2019-11-16 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with glycine at codon 180 of the TNNI3 protein (p.Asp180Gly). The aspartic acid residue is highly conserved and there is a moderate physicochemical difference between aspartic acid and glycine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in several individuals affected with left ventricular noncompaction or dilated cardiomyopathy (PMID: 21483645, 21533915, 20215591, 23785128). ClinVar contains an entry for this variant (Variation ID: 403557). 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 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.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV001528409 SCV001740122 uncertain significance not provided no assertion criteria provided clinical testing

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