The p.K360N variant (also known as c.1080G>C), located in coding exon 12 of the MYBPC3 gene, results from a G to C substitution at nucleotide position 1080. The lysine at codon 360 is replaced by asparagine, an amino acid with similar properties. This alteration has been reported in a hypertrophic cardiomyopathy (HCM) cohort (Walsh R et al. Genet Med, 2017 Feb;19:192-203). This amino acid position is well 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.

p.Lys360Asn (AAG>AAC): c.1080 G>C in exon 12 of the MYBPC3 gene (NM_000256.3). A variant of unknown significance has been identified in the MYBPC3 gene. The K360N variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The K360N variant was not observed in approximately 6,400 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The K360N variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. Additionally, this substitution occurs at a position that is class conserved among mammals and in silico analysis predicts this variant is probably damaging to the protein structure/function. Furthermore, missense mutations in nearby residues (L352P, P371R) have been reported in association with HCM, supporting the functional importance of this region of the protein.Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. Mutations in the MYBPC3 gene have been reported in 20%-30% of patients with autosomal dominant familial hypertrophic cardiomyopathy, and have been reported less frequently in patients with autosomal dominant familial dilated cardiomyopathy (CirinoAet al., 2011; Hershberger R et al., 2009). The variant is found in HCM panel(s).

This missense variant replaces lysine with asparagine at codon 360 of the MYBPC3 protein. Computational prediction tools indicate that this variant has a neutral impact on protein structure and function. 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 1/248934 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 lysine, which is basic and polar, with asparagine, which is neutral and polar, at codon 360 of the MYBPC3 protein (p.Lys360Asn). This variant is present in population databases (rs730880632, gnomAD 0.0009%). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 37652022). ClinVar contains an entry for this variant (Variation ID: 181057). 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.