Submissions for variant NM_000256.3(MYBPC3):c.46C>T (p.Pro16Ser) (rs730880573)

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Total submissions: 3

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Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000158175	SCV000208110	likely pathogenic	not provided	2014-04-24	criteria provided, single submitter	clinical testing	This variant is denoted p.Pro16Ser (CCA>TCA): c.46 C>T in exon 2 of the MYBPC3 gene (NM_000256.3). A P16S variant that is likely pathogenic was identified in the MYBPC3 gene. It has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The P16S variant was not observed 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 P16S 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. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Missense mutations in nearby residues (K7R, S18L) have been reported in association with DCM, supporting the functional importance of this region of the protein. Therefore, this variant is a strong candidate for a pathogenic mutation, however the possibility that it is a benign variant cannot be excluded. The variant is found in CARDIOMYOPATHY panel(s).
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine	RCV000609824	SCV000712383	uncertain significance	not specified	2016-07-26	criteria provided, single submitter	clinical testing	The p.Pro16Ser variant in MYBPC3 has not been previously reported in individuals with cardiomyopathy, but has been identified in 1/47636 European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP r s730880573). Computational prediction tools and conservation analysis suggest th at the p.Pro16Ser variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, the clinical signific ance of the p.Pro16Ser variant is uncertain.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute	RCV000158175	SCV000987400	uncertain significance	not provided		criteria provided, single submitter	clinical testing

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