ClinVar Miner

Submissions for variant NM_000364.4(TNNT2):c.755C>T (p.Ala252Val) (rs369181536)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 5
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000154521 SCV000204193 uncertain significance not specified 2018-04-09 criteria provided, single submitter clinical testing proposed classification - variant undergoing re-assessment, contact laboratory
Invitae RCV000466013 SCV000541911 uncertain significance Familial hypertrophic cardiomyopathy 2; Left ventricular noncompaction 6; Familial restrictive cardiomyopathy 3 2016-12-16 criteria provided, single submitter clinical testing This sequence change replaces alanine with valine at codon 245 of the TNNT2 protein (p.Ala245Val). The alanine residue is moderately conserved and there is a small physicochemical difference between alanine and valine. This variant is present in population databases (rs369181536, ExAC 0.001%). This variant has been reported in an individual affected with dilated cardiomyopathy (PMID: 24503780). ClinVar contains an entry for this variant (Variation ID: 177873). 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 tolerated, but these predictions have not been confirmed by published functional studies. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may alter RNA splicing, but this prediction has not been confirmed by published transcriptional studies. In summary, this variant is a rare missense change with uncertain impact on protein function. It has been reported in both the population and affected individuals, but the available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
GeneDx RCV000766828 SCV000618573 uncertain significance not provided 2019-01-11 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the TNNT2 gene. The c.734 C>T (A245V) variant has been previously reported in association with DCM (Bick et al., 2012; Pugh et al., 2014; Walsh et al., 2017). This variant was first reported in a 69 year-old individual from the offspring cohort of Framingham Heart Study who had features of DCM, including an increased left ventricular diastolic diameter and left atrial diameter, and decreased fractional shortening (Bick et al., 2012). Pugh et al. (2014) also reported this variant in a 53 year-old Caucasian female with a clinical diagnosis and family history of DCM, and no history of skeletal myopathy. Additionally, Chanvat et al. (2016) identified c.734 C>T in their cohort of patients with cardiomyopathy or arrhythmia, although further clinical details describing this patient's specific phenotype were not provided. Thus far, no segregation data are available for any of these published cases. Nevertheless, the c.734 C>T variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server).The c.734 C>T substitution is located in exon 14, and may be functionally significant at mRNA or protein level. At the mRNA level, c.734 C>T occurs at a nucleotide that is conserved across species, and in silico splice prediction algorithms predict this variant may create a cryptic splice donor site upstream of the natural splice donor site in intron 14 and may impact gene splicing. However, in the absence of functional mRNA studies, the physiological consequence of this variant cannot be precisely determined. At the protein level, A245V is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Additionally, although this amino acid substitution occurs at a position that is conserved in mammals, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function.
Blueprint Genetics RCV000766828 SCV000927758 likely pathogenic not provided 2018-06-21 criteria provided, single submitter clinical testing
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute RCV000845317 SCV000987359 uncertain significance Familial dilated cardiomyopathy criteria provided, single submitter clinical testing

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.