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.

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3B. 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. Heterozygous variants are frequently reported in adult onset conditions, however recessive inheritance results in a more severe early onset phenotype (OMIM). (I) 0200 - Variant is predicted to result in a missense amino acid change from proline to leucine. (I) 0251 - Variant is heterozygous. (I) 0302 - Variant is present in gnomAD <0.001 for a dominant condition (11 heterozygotes, 0 homozygotes). (SP) 0502 - Missense variant with conflicting in silico predictions and/or uninformative conservation. Conflicting in silico and moderate conservation. (I) 0600 - Variant is located in an annotated domain or motif, C1 domain; PMID: 20624503. (I) 0705 - No comparable variants have previous evidence for pathogenicity. (I) 0808 - Previous reports of pathogenicity are conflicting. This variant has been reported as either VUS, likely pathogenic or pathogenic in patients with hypertrophic cardiomyopathy and dilated cardiomyopathy. (ClinVar, Cardiodb, PMID: 20624503, 27600940, 28416588). (I) 0905 - No 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. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

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.

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.

The p.Pro186Leu variant in MYBPC3 has been reported in 1 individual with HCM (Millat 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 variant is uncertain.

In silico analysis indicates 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, 34426522, 35653365, 20800588, 27885498, 20624503, 30775854, 32841044, 33495596, 37652022)

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. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in 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.

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, 27885498, 28416588, 29875424, 37652022; internal data). 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.