Submissions for variant NM_000256.3(MYBPC3):c.1546G>A (p.Glu516Lys)

dbSNP: rs730880545

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000158099	SCV000208034	uncertain significance	not provided	2014-05-13	criteria provided, single submitter	clinical testing	p.Glu516Lys (GAG>AAG): c.1546 G>A in exon 17 of the MYBPC3 gene (NM_000256.3). A variant of unknown significance has been identified in the MYBPC3 gene. The E516K variant has not been published as a mutation or as a benign polymorphism to our knowledge. The E516K variant was not observed in approximately 6400 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 E516K 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 in mammals and class conserved across species. Missense mutations in nearby residues (G507R, A522T) have been reported in association with HCM, supporting the functional importance of this region of the protein. Nevertheless, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. 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 HCM, and have been reported less frequently in patients with autosomal dominant familial DCM (CirinoAet al., 2011; Hershberger R et al., 2009). The variant is found in CARDIOMYOPATHY panel(s).
Ambry Genetics	RCV000618008	SCV000737375	uncertain significance	Cardiovascular phenotype	2024-11-20	criteria provided, single submitter	clinical testing	The p.E516K variant (also known as c.1546G>A), located in coding exon 17 of the MYBPC3 gene, results from a G to A substitution at nucleotide position 1546. The glutamic acid at codon 516 is replaced by lysine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear.
Color Diagnostics, LLC DBA Color Health	RCV001178349	SCV001342764	uncertain significance	Cardiomyopathy	2023-03-24	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with lysine at codon 516 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 not been reported in individuals affected with MYBPC3-related disorders in the literature. This variant has been identified in 8/249246 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001850205	SCV002186247	uncertain significance	Hypertrophic cardiomyopathy	2023-06-21	criteria provided, single submitter	clinical testing	ClinVar contains an entry for this variant (Variation ID: 180942). This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 516 of the MYBPC3 protein (p.Glu516Lys). This variant is present in population databases (rs730880545, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with MYBPC3-related conditions. 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.
All of Us Research Program, National Institutes of Health	RCV001850205	SCV004834605	uncertain significance	Hypertrophic cardiomyopathy	2023-08-08	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with lysine at codon 516 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). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 8/249246 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.
Mayo Clinic Laboratories, Mayo Clinic	RCV000158099	SCV005412324	uncertain significance	not provided	2023-12-12	criteria provided, single submitter	clinical testing