ClinVar Miner

Submissions for variant NM_000364.4(TNNT2):c.341C>T (p.Ala114Val) (rs727504245)

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 RCV000154215 SCV000203868 uncertain significance not specified 2017-08-15 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Pathogenic. The p.Ala104Val variant in TNNT2 has been identified in 4 individuals with HCM (Nakajima-Tanigu chi 1997, Pasquale 2012, LMM data). It has also been identified in 1/8654 East A sian chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadins titute.org; dbSNP rs727504245). In vitro functional studies provide some evidenc e that the p.Ala104Val variant may impact protein function (Palm 2001, Harada 20 04). However, these types of assays may not accurately represent biological func tion. This variant was also predicted to be pathogenic using a computational too l clinically validated by our laboratory. This tool's pathogenic prediction is e stimated to be correct 94% of the time (Jordan 2011). In summary, while there is some suspicion for a pathogenic role, the clinical significance of the p.Ala104 Val variant is uncertain.
Invitae RCV000476946 SCV000541918 likely pathogenic Familial hypertrophic cardiomyopathy 2; Left ventricular noncompaction 6; Familial restrictive cardiomyopathy 3 2018-12-10 criteria provided, single submitter clinical testing This sequence change replaces alanine with valine at codon 104 of the TNNT2 protein (p.Ala104Val). The alanine residue is weakly conserved and there is a small physicochemical difference between alanine and valine. This variant is present in population databases (rs727504245, ExAC 0.01%). This variant has been reported in several individuals affected with hypertrophic cardiomyopathy (PMID: 9140840, 27532257, 28408708). This variant has been also been observed in two additional individuals with hypertrophic cardiomyopathy (PMID: 23396983). However, in those individuals pathogenic alleles were also identified in different genes, which suggests that this c.311C>T variant was not the primary cause of disease. ClinVar contains an entry for this variant (Variation ID: 177633). A computational algorithm designed to assess the pathogenicity of variants in TNNT2 with regard to hypertrophic cardiomyopathy predicted this sequence change to be deleterious. The algorithm has a sensitivity of 94% and a specificity of 89% (PMID: 21310275). 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. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute RCV000845306 SCV000987347 likely pathogenic Primary familial hypertrophic cardiomyopathy criteria provided, single submitter clinical testing
Agnes Ginges Centre for Molecular Cardiology,Centenary Institute RCV000853450 SCV000996361 uncertain significance Bicuspid aortic valve 2017-04-19 criteria provided, single submitter research

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.