Submissions for variant NM_000256.3(MYBPC3):c.3599T>C (p.Leu1200Pro)

dbSNP: rs397516028

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000035600	SCV000059251	likely pathogenic	Primary dilated cardiomyopathy	2011-01-31	criteria provided, single submitter	clinical testing
Laboratory of Genetics and Molecular Cardiology, University of São Paulo	RCV000201471	SCV000256172	likely pathogenic	Hypertrophic cardiomyopathy 4		criteria provided, single submitter	clinical testing
GeneDx	RCV000494008	SCV000582015	uncertain significance	not provided	2020-01-20	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 25335496, 15519027, 20031619, 24093860, 28790153, 22907696)
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000770323	SCV000901757	likely pathogenic	Cardiomyopathy	2016-07-27	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001852724	SCV002295143	uncertain significance	Hypertrophic cardiomyopathy	2021-10-06	criteria provided, single submitter	clinical testing	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. 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. ClinVar contains an entry for this variant (Variation ID: 42725). This missense change has been observed in individual(s) with clinical features of MYBPC3-related conditions (PMID: 20031619, 24093860, 28790153). This variant is not present in population databases (ExAC no frequency). This sequence change replaces leucine with proline at codon 1200 of the MYBPC3 protein (p.Leu1200Pro). The leucine residue is highly conserved and there is a moderate physicochemical difference between leucine and proline.
Ambry Genetics	RCV003298049	SCV003989417	uncertain significance	Cardiovascular phenotype	2023-05-08	criteria provided, single submitter	clinical testing	The p.L1200P variant (also known as c.3599T>C), located in coding exon 32 of the MYBPC3 gene, results from a T to C substitution at nucleotide position 3599. The leucine at codon 1200 is replaced by proline, an amino acid with similar properties. This variant has been detected in hypertrophic cardiomyopathy cohorts (Marsiglia JD et al. Am Heart J, 2013 Oct;166:775-82; Burns C et al. Circ Cardiovasc Genet, 2017 Aug;10; Helms AS et al. Circ Genom Precis Med, 2020 Oct;13:396-405). This variant co-occurred with an MYBPC3 mutation in a pediatric case with severe HCM (Demo EM et al. J Cardiovasc Transl Res, 2009 Dec;2:500-7), and also co-occurred with an MYBPC3 mutation in a case with neonatal heart failure and and left ventricular noncompaction (Dellefave LM et al. Circ Cardiovasc Genet, 2009 Oct;2:442-9). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000201471	SCV005400190	likely pathogenic	Hypertrophic cardiomyopathy 4	2023-07-16	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with hypertrophic cardiomyopathy 4 (MIM#115197). (I) 0108 - This gene is associated with both recessive and dominant disease. Dominant inheritance is frequently reported in adult onset conditions and recessive inheritance results in a more severe early onset phenotype (OMIM). (I) 0115 - Variants in this gene are known to have variable expressivity (PMID: 32841044). (I) 0200 - Variant is predicted to result in a missense amino acid change from leucine to proline. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated immunoglobulin I-set domain (DECIPHER). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported as pathogenic, likely pathogenic and a VUS in the literature and ClinVar. It has been reported in at least six unrelated individuals with hypertrophic cardiomyopathy (HCM) and one individual with cardiomyopathy, including two with neonatal heart failure or childhood-onset severe HCM who each had a second MYBPC3 variant (PMIDs: 20031619, 20560008, 24093860, 32841044, personal communication with Invitae and GeneDx). In addition, it has been reported in the UK Biobank, however no further clinical information is available for the relevant individual(s) (PMID: 30665703). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign