The c.994G>A (p.E332K) alteration is located in exon 12 (coding exon 12) of the MYBPC3 gene. This alteration results from a G to A substitution at nucleotide position 994, causing the glutamic acid (E) at amino acid position 332 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

This missense variant replaces glutamic acid with lysine at codon 332 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 an individual affected with hypertrophic cardiomyopathy (PMID: 27532257). It has also been reported in individuals affected with dilated cardiomyopathy; one of these individuals also carried a pathogenic variant in the MYH7 gene (PMID: 24503780, 27532257). This variant has been identified in 8/246592 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 E332K variant in the MYBPC3 gene has been reported as a variant of uncertain significance in association with DCM (Pugh et al., 2014). Pugh et al. (2014) identified the E332K variant in two unrelated individuals with a clinical and family history of DCM, one of whom also harbored a likely pathogenic variant in the MYH7 gene. The E332K variant has been also reported as a pathogenic variant, but clinical information was not provided (Zimmerman R et al., 2010). The E332K 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 E332K variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across mammals. In silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.

Variant classified as Uncertain Significance - Favor Benign. The p.Glu332Lys variant in MYBPC3 has been reported in 2 individuals with DCM and 1 individual with HCM, one of whom carried an additional pathogenic variant in MYBPC3 (Walsh 2017, LMM data). It did not segregate with disease in 1 affected family member with DCM (LMM data). It has also been identified in 0.02% (7/34248) of Latino chromosomes by gnomAD (http://gnomad.broadinstitute.org) and reported in ClinVar (Variation ID #42815). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, while the clinical significance of this variant is uncertain, these data suggest that it is more likely to be benign. ACMG/AMP Criteria applied: PP3, BS1_Supporting, BS4.

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. 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. ClinVar contains an entry for this variant (Variation ID: 42815). This missense change has been observed in individuals with hypertrophic cardiomyopathy and dilated cardiomyopathy (PMID: 27532257). This variant is present in population databases (rs397516086, gnomAD 0.02%). This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 332 of the MYBPC3 protein (p.Glu332Lys).

This missense variant replaces glutamic acid with lysine at codon 332 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 an individual affected with hypertrophic cardiomyopathy (PMID: 27532257). It has also been reported in individuals affected with dilated cardiomyopathy; one of these individuals also carried a pathogenic variant in the MYH7 gene (PMID: 24503780, 27532257). This variant has been identified in 8/246592 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.