ClinVar Miner

Submissions for variant NM_000256.3(MYBPC3):c.481C>A (p.Pro161Thr) (rs397516053)

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 RCV000035634 SCV000059285 uncertain significance not specified 2017-08-30 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Pathogenic. The p.Pro161Thr variant in MYBPC3 has been reported in 4 individuals with HCM (Kapplinger 2014, LMM data). This variant has been reported in ClinVar (Variant ID 42759). This v ariant has been identified in 1/68078 European chromosomes by the Genome Aggrega tion Database (gnomAD, http://gnomad.broadinstitute.org). Computational predicti on tools and conservation analysis suggest that the p.Pro161Thr variant may impa ct the protein, though this information is not predictive enough to determine pa thogenicity. In summary, while there is some suspicion for a pathogenic role, th e clinical significance of the p.Pro161Thr variant is uncertain.
GeneDx RCV000766309 SCV000208219 uncertain significance not provided 2018-10-03 criteria provided, single submitter clinical testing The P161T variant of uncertain significance in the MYBPC3 gene has been reported previously in three individuals with a diagnosis of HCM or who were referred for HCM genetic testing; however, the veracity of the diagnoses was not confirmed, and additional clinical information and segregation information was not provided (Kapplinger et al., 2014). This variant has also been identified independently and/or in conjunction with additional cardiogenetic variants in individuals referred for HCM genetic testing at GeneDx; however, thus far, segregation data is limited or absent for these individuals due to the lack of clinical information provided and/or insufficient participation by informative family members. Additionally, it is classified in ClinVar as a variant of uncertain significance in association with HCM by two other clinical laboratories (ClinVar SCV000059285.4, SCV000284246.1; Landrum et al., 2016). The P161T variant was not observed in 427 published control individuals or in approximately 6,200 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The P161T variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Additionally, this substitution occurs at a position that is conserved across species. Consequently, in silico analysis predicts this variant is probably damaging to the protein structure/function. Although a missense variant in the same residue (P161S) and missense variants in nearby residues have been reported in the Human Gene Mutation Database (Stenson et al., 2014) in association with HCM, their pathogenicity has not been definitively determined.Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or benign.
Invitae RCV000228800 SCV000284246 uncertain significance Hypertrophic cardiomyopathy 2020-07-08 criteria provided, single submitter clinical testing This sequence change replaces proline with threonine at codon 161 of the MYBPC3 protein (p.Pro161Thr). The proline residue is highly conserved and there is a small physicochemical difference between proline and threonine. This variant is present in population databases (rs397516053, ExAC <0.01%). This variant has been observed in individuals affected with hypertrophic cardiomyopathy (PMID: 24510615, 24793961, 27532257). ClinVar contains an entry for this variant (Variation ID: 42759). 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. 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.
Ambry Genetics RCV000244834 SCV000319960 likely pathogenic Cardiovascular phenotype 2017-10-12 criteria provided, single submitter clinical testing The p.P161T variant (also known as c.481C>A), located in coding exon 4 of the MYBPC3 gene, results from a C to A substitution at nucleotide position 481. The proline at codon 161 is replaced by threonine, an amino acid with highly similar properties. In one study of individuals who underwent genetic testing for hypertrophic cardiomyopathy (HCM), this variant was observed in three individuals, one of whom had a clinical diagnosis of HCM as well as a positive family history; however, clinical details for the other two individuals were not available (Kapplinger JD et al. J Cardiovasc Transl Res. 2014;7(3):347-61; pers. comm.). Another alteration at this same amino acid position, p.P161S (c.481C>T), has also been reported in an individual with HCM (Alders M et al. Eur Heart J. 2003;24(20):1848-53). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute RCV000627141 SCV000747958 likely pathogenic Primary familial hypertrophic cardiomyopathy 2017-06-29 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.