Variant classified as Uncertain Significance - Favor Pathogenic. The p.Val178Met variant in MYBPC3 has been reported in at least 3 individuals with HCM (Ho 2009 ; LMM data), one of which carried this variant in the homozygous state. This va riant also segregated with disease in 1 affected relative. This variant has been identified in 1/105830 European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org/). This variant has been reported in C linVar (Variant ID: 174794). Computational prediction tools and conservation ana lysis suggest that the p.Val178Met variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, whi le there is some suspicion for a pathogenic role, the clinical significance of t he p.Val178Met variant is uncertain.

This missense variant replaces valine with methionine at codon 178 of the MYBPC3 protein. Computational prediction tools indicate that this variant has a deleterious impact on protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in several individuals affected with hypertrophic cardiomyopathy (PMID: 20031602, 24111713, 33495597, 36293497, 36788754). It has also been reported in an individual affected with an unspecified cardiomyopathy (PMID: 30165862) and in an individual affected with left ventricular noncompaction (PMID: 30471092). This variant has not been identified 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.V178M variant (also known as c.532G>A), located in coding exon 5 of the MYBPC3 gene, results from a G to A substitution at nucleotide position 532. The valine at codon 178 is replaced by methionine, an amino acid with highly similar properties. This variant was reported in individual(s) with features consistent with hypertrophic cardiomyopathy (HCM), left ventricular non-compaction (LVNC), and general cardiomyopathy cohorts; however, limited clinical information was provided and additional cardiac variants were detected in some cases (Ho CY et al. Circ Cardiovasc Genet, 2009 Aug;2:314-21; Berge KE et al. Clin. Genet., 2014 Oct;86:355-60; Walsh R et al. Genet. Med., 2017 02;19:192-203; Mademont-Soler I et al. PLoS One, 2017 Aug;12:e0181465; Viswanathan SK et al. PLoS ONE, 2017 Dec;12:e0187948; Lu C et al. J Transl Med, 2018 08;16:241; Richard P et al. Clin. Genet., 2019 Mar;95:356-367). 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 missense variant replaces valine with methionine at codon 178 of the MYBPC3 protein. Computational prediction tools indicate that this variant has a deleterious impact on protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in several individuals affected with hypertrophic cardiomyopathy (PMID: 20031602, 24111713, 33495597, 36293497, 36788754). It has also been reported in an individual affected with an unspecified cardiomyopathy (PMID: 30165862) and in an individual affected with left ventricular noncompaction (PMID: 30471092). This variant has not been identified 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 valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 178 of the MYBPC3 protein (p.Val178Met). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with clinical features of hypertrophic cardiomyopathy (HCM) as well as in individual(s) with left ventricular noncompaction cardiomyopathy and left ventricular noncompaction cardiomyopathy. However, in at least one individual pathogenic allele[s] were also identified in MYBPC3 and/or HCN4, which suggests that this c.532G>A variant may not be the primary cause of disease. (PMID: 20031602, 24111713, 27532257, 29121657, 30165862, 30471092, 34088380; internal data). ClinVar contains an entry for this variant (Variation ID: 164149). 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 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.