ClinVar Miner

Submissions for variant NM_000363.5(TNNI3):c.509G>A (p.Arg170Gln) (rs727503503)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 4
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare 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20 09) and was identified by our laboratory in 6 individuals with early onset RCM, including 3 de novo occurrences (LMM unpublished data).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 2017-04-21 criteria provided, single submitter clinical testing The Arg170Gln mutation in the TNNI3 gene has been published previously in one individual with HCM (Kaski J et al., 2009). This study reported that Arg170Gln, which is located within the actin-binding domain of the troponin I protein, is predicted to increase the inhibitory effect of troponin I. Mutations affecting neighboring codons (Lys164Thr, Ser166Phe, Lys167Pro, Ala171Thr, Lys178Glu) have been reported in association with HCM and restrictive cardiomyopathy, further supporting the functional importance of this region of the protein. Furthermore, the NHLBI ESP Exome Variant Server reports Arg170Gln was not observed in approximately 6000 samples from individuals of European and African American backgrounds, indicating it is not a common benign variant in these populations. The Arg170Gln mutation has been observed in multiple other unrelated individual tested for HCM at GeneDx.Therefore, Arg170Gln in the TNNI3 gene is interpreted as a disease-causing mutation.The variant is found in HCM panel(s).
Invitae RCV000540068 SCV000623788 pathogenic Hypertrophic cardiomyopathy 2020-10-05 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 170 of the TNNI3 protein (p.Arg170Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in several individuals affected with hypertrophic cardiomyopathy (PMID: 20031618, 27532257). This variant has also been shown to arise de novo in an individual affected with restrictive cardiomyopathy (PMID: 25940119). ClinVar contains an entry for this variant (Variation ID: 165516). 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. For these reasons, this variant has been classified as Pathogenic.
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.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.