The MYBPC3 c.1072G>A variant is predicted to result in the amino acid substitution p.Asp358Asn. This variant has been reported in an individual with hypertrophic cardiomyopathy as part of a large cohort study (Table S1A, Walsh et al 2017. PubMed ID: 27532257). This variant is reported in 0.016% of alleles in individuals of European (Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/11-47367776-C-T). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

This missense variant replaces aspartic acid with asparagine at codon 358 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 individuals affected with hypertrophic cardiomyopathy (PMID: 25351510, 27532257, 33495597). This variant has been identified in 10/280354 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.

PM2, PS4_supp, BP4

The p.D358N variant (also known as c.1072G>A), located in coding exon 12 of the MYBPC3 gene, results from a G to A substitution at nucleotide position 1072. The aspartic acid at codon 358 is replaced by asparagine, an amino acid with highly similar properties. This variant has been reported in hypertrophic cardiomyopathy cohorts; however, clinical details were limited (Lopes LR et al. Heart. 2015;101:294-301; Walsh R et al. Genet Med. 2017 02;19(2):192-203). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

Identified in patients with HCM in published literature (PMID: 25351510, 37652022, 27532257); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 27532257, 37937776, 25351510, 37652022)

This variant is classified as VUS-3B. Evidence in support of pathogenic classification: Variant is present in gnomAD <0.01 (v4: 104 heterozygote(s), 0 homozygote(s)). Evidence in support of benign classification: Missense variant predicted to be tolerated by in silico tool(s) or not conserved in placental mammals with a minor amino acid change. Additional information: Variant is predicted to result in a missense amino acid change from aspartic acid to asparagine; This variant is heterozygous; This gene is associated with both recessive and dominant disease. Dominant inheritance is frequently reported with an adult onset phenotype, and recessive inheritance with a more severe early onset phenotype (OMIM); Alternative amino acid change(s) at the same position are present in gnomAD (Highest allele count: v2: 4 heterozygote(s), 0 homozygote(s)); Previous evidence of pathogenicity for this variant is inconclusive. This variant has been classified as a VUS by clinical laboratories in ClinVar. It has also been reported in the literature in individuals with HCM and/or sudden death; however, it has been classified as a VUS in all reports (PMIDs: 25351510, 33495597, 27532257, 37937776); No published segregation evidence has been identified for this variant; No published functional evidence has been identified for this variant; Another missense variant comparable to the one identified in this case has inconclusive previous evidence for pathogenicity. The p.(Asp358Glu) variant has been classified as a VUS by clinical laboratories in ClinVar, and reported in the literature in individuals with idiopathic atrioventricular conduction disease and dilated cardiomyopathy (PMIDs: 36352534, 32041989); Variant is not located in an established domain, motif, hotspot or informative constraint region; Loss of function is a known mechanism of disease in this gene and is associated with hypertrophic cardiomyopathy 4 (MIM#115197); Variants in this gene are known to have variable expressivity (PMID: 32841044); Inheritance information for this variant is not currently available in this individual.

This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 358 of the MYBPC3 protein (p.Asp358Asn). This variant is present in population databases (rs746267533, gnomAD 0.02%). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy and/or MYBPC3-related conditions (PMID: 25351510, 27532257, 37652022, 37937776). ClinVar contains an entry for this variant (Variation ID: 407328). 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 tolerated. 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 aspartic acid with asparagine at codon 358 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: 25351510, 27532257, 33495597) or sudden cardiac death (PMID: 37937776). This variant has been identified in 104/1613802 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.