Submissions for variant NM_000256.3(MYBPC3):c.557C>T (p.Pro186Leu)

gnomAD frequency: 0.00004  dbSNP: rs727503216

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000151163	SCV000198964	uncertain significance	not specified	2014-09-05	criteria provided, single submitter	clinical testing	The Pro186Leu variant in MYBPC3 has been reported in 1 individual with HCM (Mill at 2010) and was absent from large population studies. Computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. In summary, the clinical significance of the Pro186Leu va riant is uncertain.
GeneDx	RCV000766311	SCV000208229	uncertain significance	not provided	2023-09-16	criteria provided, single submitter	clinical testing	Reported in several patients with cardiomyopathy, however, at least two reported individuals harbor co-occurring likely pathogenic or pathogenic variants that may explain their phenotype (Millat et al., 2010; Walsh et al., 2017; Dal Ferro et al., 2017; Mazzarotto et al., 2018; Yeh et al., 2019); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 27532257, 27600940, 24793961, 28416588, Niyazova2019[article], 31879508, 29875424, 20624503, 34426522, 35653365)
Color Diagnostics, LLC DBA Color Health	RCV000777987	SCV000914093	uncertain significance	Cardiomyopathy	2023-10-19	criteria provided, single submitter	clinical testing	This missense variant replaces proline with leucine at codon 186 of the MYBPC3 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in multiple individuals affected with hypertrophic cardiomyopathy (PMID: 20624503, 20800588, 27600940, 27885498, 29875424, 30775854, 32841044, 33495596, ClinVar SCV000925171.1). This variant has been identified in 11/243662 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Blueprint Genetics	RCV000766311	SCV000927405	uncertain significance	not provided	2017-09-11	criteria provided, single submitter	clinical testing
Invitae	RCV000801763	SCV000941557	likely pathogenic	Hypertrophic cardiomyopathy	2023-12-24	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 186 of the MYBPC3 protein (p.Pro186Leu). This variant is present in population databases (rs727503216, gnomAD 0.02%). This missense change has been observed in individuals with hypertrophic cardiomyopathy or dilated cardiomyopathy (PMID: 20624503, 27532257, 28416588, 29875424; Invitae). ClinVar contains an entry for this variant (Variation ID: 164147). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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.
Petrovsky National Research Centre of Surgery, The Federal Agency for Scientific Organizations	RCV001263458	SCV001441525	uncertain significance	Primary dilated cardiomyopathy; Left ventricular noncompaction cardiomyopathy	2020-10-15	criteria provided, single submitter	clinical testing	We observed the c.557C>T (p.P186L) in MYBPC3 gene in a female 30-y.o. proband diagnosed with left ventricular noncompaction and dilated cardiomyopathy. The proband also carried a p.W1214* variant in MYBPC3 gene. The family was unavailable for screening. The frequency of p.P186L genetic variant, according to gnomAD, is 4,514e-5, which makes it rare. According to bioinformatic online resources, the p.P186L genetic variant is probably pathogenic. However, in the absence of familial screening and functional studies we assume that the p.P186L genetic variant could only be classified as a variant of uncertain clinical significance.
Ambry Genetics	RCV002345464	SCV002647336	uncertain significance	Cardiovascular phenotype	2022-11-22	criteria provided, single submitter	clinical testing	The p.P186L variant (also known as c.557C>T), located in coding exon 5 of the MYBPC3 gene, results from a C to T substitution at nucleotide position 557. The proline at codon 186 is replaced by leucine, an amino acid with similar properties. This variant has been reported in hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM) cohorts, as well as in an HCM genetic testing cohort; however, clinical details have been limited (Millat G et al. Eur J Med Genet 2010 Jul;53:261-7; Dal Ferro M et al. Heart, 2017 11;103:1704-1710; Walsh R et al. Genet Med, 2017 02;19:192-203; Walsh R et al. Genet. Med., 2017 02;19:192-203; Mazzarotto F et al. Genet. Med., 2019 02;21:284-292). This variant has also been reported in the Framingham Heart Study cohort; however, clinical details were limited (Bick AG et al. Am J Hum Genet, 2012 Sep;91:513-9). This alteration has also been reported in whole exome sequencing cohorts (Retterer K et al. Genet Med, 2016 Jul;18:696-704; Kars ME et al. Proc Natl Acad Sci U S A, 2021 Sep;118:). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000777987	SCV003837602	uncertain significance	Cardiomyopathy	2021-08-05	criteria provided, single submitter	clinical testing
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000766311	SCV000925171	uncertain significance	not provided	2016-04-27	no assertion criteria provided	provider interpretation	- p.Pro186Leu (c.557C>T) in the MYBPC3 gene Given the lack of case data we consider this variant to be of unknown significance and we do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). We have seen this variant in 1 patient with HCM. Testing was done at ARUP. Millat et al., 2010 reported the P186L variant in one person with HCM. No additional clinical data was provided. The ARUP lab report notes that the proline at codon 186 is only moderately conserved among species. In silico analysis with SIFT predicts the variant to be damaging, PolyPhen-2 predicts the variant to be possibly damaging, and Mutation Taster predicts it to be disease causing. This variant is listed in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/), which currently includes variant calls on ~64,000 individuals of European, African, Latino and Asian descent (as of 4/27/2016). It was seen in 5 of 52,475 individuals, specifically in 2 of 3866 East Asian individuals, 1 of 3773 African individuals, and 2 of 29,548 non-Finnish European individuals. The average coverage at that site in ExAC is moderate, ranging from 10x with peaks at 15x and 25x.