Submissions for variant NM_000363.5(TNNI3):c.509G>A (p.Arg170Gln)

dbSNP: rs727503503

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000152076	SCV000200714	pathogenic	Restrictive cardiomyopathy; Hypertrophic cardiomyopathy	2015-03-04	criteria provided, single submitter	clinical testing	The p.Arg170Gln variant in TNNI3 has been reported in 1 child with HCM (Kaski 20 09) and was identified by our laboratory in 6 individuals with early onset RCM, including 3 de novo occurrences (LMM unpublished data). This variant was absent from large population studies. Of note, RCM is thought to represent a rare prese ntation of the clinical spectrum of HCM and has so far been associated with vari ants in the MYH7 and TNNI3 genes (Kubo 2007). In summary, this variant meets ou r criteria to be classified as pathogenic for RCM in an autosomal dominant manne r based on multiple de novo occurrences in individuals with RCM.
GeneDx	RCV000159232	SCV000209178	pathogenic	not provided	2021-09-02	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (Lek et al., 2016); Reported as pathogenic in ClinVar (ClinVar Variant ID #165516; Landrum et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27532257, 28031081, 20031618, 31737537, 33336002, 32420109, 25940119)
Invitae	RCV000540068	SCV000623788	pathogenic	Hypertrophic cardiomyopathy	2023-02-18	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 170 of the TNNI3 protein (p.Arg170Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 20031618, 25940119, 27532257). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 165516). 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. For these reasons, this variant has been classified as Pathogenic.
Revvity Omics, Revvity	RCV000159232	SCV002022363	pathogenic	not provided	2023-08-08	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV003343657	SCV004052007	likely pathogenic	Cardiovascular phenotype	2023-07-06	criteria provided, single submitter	clinical testing	The p.R170Q variant (also known as c.509G>A), located in coding exon 7 of the TNNI3 gene, results from a G to A substitution at nucleotide position 509. The arginine at codon 170 is replaced by glutamine, an amino acid with highly similar properties. This alteration has been reported in multiple individuals with hypertrophic cardiomyopathy (HCM) and restrictive cardiomyopathy (RCM), including a de novo occurrence in an individual with RCM (Kaski JP et al. Circ Cardiovasc Genet, 2009 Oct;2:436-41; Mouton JM et al. Cardiovasc J Afr, 2015;26:63-9; Ross SB et al. Circ Cardiovasc Genet, 2017 Jun;10:[ePub ahead of print]; Walsh R et al. Genet Med, 2017 Feb;19:192-203; Marschall C et al. Cardiovasc Diagn Ther, 2019 Oct;9:S292-S298; Marey I et al. Open Med (Wars), 2020 May;15:435-446; Stava TT et al. Eur J Prev Cardiol, 2022 Oct;29:1789-1799). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this variant is expected to be causative of autosomal dominant TNNI3-related cardiomyopathy; however, its clinical significance for autosomal recessive TNNI3-related dilated cardiomyopathy is unclear.
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000159232	SCV000280510	likely pathogenic	not provided	2013-10-16	no assertion criteria provided	clinical testing	Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. p.Arg170Gln (c.509 G>A) in the TNNI3 gene We have seen this variant in a patient diagnosed at age 3 with RCM, s/p heart transplant. p.Arg170Gln has been reported in 1 pediatric HCM proband (Kaski 2009) and at the testing lab has been seen it in 7 individuals with early-onset RCM (including our patient). Two were de novo. TNNI3 is a gene strongly associated with RCM (Kubo 2007). This variant was not identified in large population studies, also supporting pathogenicity.