ClinVar Miner

Submissions for variant NM_000256.3(MYBPC3):c.2449C>T (p.Arg817Trp) (rs727503188)

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
Fulgent Genetics,Fulgent Genetics RCV000763241 SCV000893877 pathogenic Familial hypertrophic cardiomyopathy 4; Left ventricular noncompaction 10 2018-10-31 criteria provided, single submitter clinical testing
GeneDx RCV000485850 SCV000565277 likely pathogenic not provided 2014-11-17 criteria provided, single submitter clinical testing A novel R817W variant that is likely pathogenic was identified in the MYBPC3 gene. It has not been published as a pathogenic variant, nor has it been reported as a benign polymorphism to our knowledge. The R817W variant was not observed in approximately 6,400 individuals of European and African American ancestry in an external variant database, indicating it is not a common benign variant in these populations. The R817W 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 and in silico analysis predicts this variant is probably damaging to the protein structure/function. Furthermore, missense variants in nearby residues (R820Q, R820W, K811R, R810H, R810L, I807N) have been reported in the Human Gene Mutation Database in association with cardiomyopathy (Stenson et al., 2014), supporting the functional importance of this region of the protein. Therefore, this variant is a strong candidate for a pathogenic variant, however the possibility that it is a benign variant cannot be excluded.
Invitae RCV000628977 SCV000749887 likely pathogenic Hypertrophic cardiomyopathy 2018-09-21 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 817 of the MYBPC3 protein (p.Arg817Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals affected with hypertrophic cardiomyopathy (PMID: 25351510, 27532257), and has been observed to be homozygous in a pregnancy affected with nonimmune hydrops fetalis (PMID: 28749478). ClinVar contains an entry for this variant (Variation ID: 164078). 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. Variants that disrupt the p.Arg817 amino acid residue in MYBPC3 have been observed in affected individuals (PMID: 26914223, 27532257). This suggests that it is a clinically significant residue, and that other variants that disrupt this residue are likely to be causative of disease. 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.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000151096 SCV000198855 uncertain significance not specified 2013-02-12 no assertion criteria provided clinical testing proposed classification - variant undergoing re-assessment, contact laboratory

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.