ClinVar Genomic variation as it relates to human health

This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 873 of the MYBPC3 protein (p.Pro873Leu). This variant is present in population databases (rs371401403, gnomAD 0.03%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with left ventricular noncompaction or dilated cardiomyopathy (PMID: 21551322, 27173948). ClinVar contains an entry for this variant (Variation ID: 64615). 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. 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.

This missense variant replaces proline with leucine at codon 873 of the MYBPC3 protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported an individual affected with hypertrophic cardiomyopathy (PMID: 27600940) and in an individual affected with isolated left ventricular non-compaction cardiomyopathy (PMID: 21551322). It has also been reported in two individuals affected with dilated cardiomyopathy as well as in one healthy relative (PMID: 27173948, 32826072). This variant has been identified in 13/207756 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 missense variant replaces proline with leucine at codon 873 of the MYBPC3 protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported an individual affected with hypertrophic cardiomyopathy (PMID: 27600940) and in an individual affected with isolated left ventricular non-compaction cardiomyopathy (PMID: 21551322). It has also been reported in two individuals affected with dilated cardiomyopathy as well as in one healthy relative (PMID: 27173948, 32826072). This variant has been identified in 13/207756 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.

The p.P873L variant (also known as c.2618C>T), located in coding exon 26 of the MYBPC3 gene, results from a C to T substitution at nucleotide position 2618. The proline at codon 873 is replaced by leucine, an amino acid with similar properties. This variant has been detected in a patient with left ventricular noncompaction and heart failure (Probst S et al. Circ Cardiovasc Genet, 2011 Aug;4:367-74). This variant has also been reported in an individual with dilated cardiomyopathy, developmental delay and hearing loss who also had a variant in the CASK gene; however, four relatives with MYBPC3 p.P873L had normal echocardiograms (Reinstein E et al. Genet Res (Camb). 2016 05;98:e8). Additionally, this alteration was detected as a secondary cardiac variant in an exome cohort in an individual without known cardiomyopathy (Ng D et al. Circ Cardiovasc Genet, 2013 Aug;6:337-46). 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.

This mutation is denoted p.Pro873Leu (aka P873L) at the protein level and c.2618 C>T at the cDNA level. The Pro873Leu mutation in the MYBPC3 gene has been published previously in association with cardiomyopathy (Probst, 2011). Pro873Leu was reported in a 37 year old male patient with decompensated congestive heart failure, and was not present in 360 control chromosomes (Probst, 2011). Another mutation affecting the same residue (Pro873His) has also been reported in association with HCM (Probst, 2011), further supporting the functional importance of this region of the protein.The variant is found in HCM panel(s).

Variant summary: MYBPC3 c.2618C>T (p.Pro873Leu) results in a non-conservative amino acid change located in the Fibronectin type III domain (IPR003961) of the encoded protein sequence. Four of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 6.8e-05 in 176378 control chromosomes (gnomAD). The observed variant frequency is approximately two fold of the estimated maximal expected allele frequency for a pathogenic variant in MYBPC3 causing Dilated Cardiomyopathy phenotype (3.1e-05), strongly suggesting that the variant is benign. c.2618C>T has been reported in the literature in individuals affected with left ventricular noncompaction cardiomyopathy, dilated cardiomyopathy and hypertrophic cardiomyopathy (Probst_2011, Haas_2014, Reinstein_2016, Cecconi_2016, Lin_2021). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 27066506, 27600940, 25163546, 34819141, 23861362, 21551322, 27173948). Seven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly benign.