Identified in a patient with cardiomyopathy referred for genetic testing at GeneDx and reported in a patient with HCM in the published literature (Walsh et al., 2017); Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27532257)

This missense variant replaces aspartic acid with asparagine at codon 431 of the MYBPC3 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with hypertrophic cardiomyopathy (PMID: 27532257). This variant has been identified in 5/244552 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 aspartic acid to asparagine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2) <0.001 for a dominant condition (5 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (1 heterozygote, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated immunoglobin domain (PDB, NCBI). (I) 0710 - Another missense variant comparable to the one identified in this case has inconclusive previous evidence for pathogenicity. This variant (p.Asp431Glu) has been reported as a VUS (ClinVar). (I) 0808 - Previous reports of pathogenicity for this variant are conflicting. This variant has been reported as both likely pathogenic and as a VUS (ClinVar, cardiacdb). (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1205 - This variant has been shown to be maternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

This missense variant replaces aspartic acid with asparagine at codon 431 of the MYBPC3 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with hypertrophic cardiomyopathy (PMID: 27532257). This variant has been identified in 5/244552 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 aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 431 of the MYBPC3 protein (p.Asp431Asn). This variant is present in population databases (rs753321277, gnomAD 0.01%). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 27532257, 37652022). ClinVar contains an entry for this variant (Variation ID: 418353). 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.

The p.D431N variant (also known as c.1291G>A), located in coding exon 15 of the MYBPC3 gene, results from a G to A substitution at nucleotide position 1291. The aspartic acid at codon 431 is replaced by asparagine, an amino acid with highly similar properties. This variant was reported in individual(s) with features consistent with hypertrophic cardiomyopathy (Walsh R et al. Genet Med, 2017 Feb;19:192-203). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear.