Submissions for variant NM_000256.3(MYBPC3):c.2164G>A (p.Glu722Lys)

gnomAD frequency: 0.00001  dbSNP: rs730880696

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000158441	SCV000208376	uncertain significance	not provided	2017-01-30	criteria provided, single submitter	clinical testing	The E722K variant of uncertain significance in the MYBPC3 gene has not been published as pathogenic or benign to our knowledge. This variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). Furthermore, E722K has been identified in another individual referred for cardiomyopathy genetic testing at GeneDx; however, thus far, segregation data is limited for this individual due to the lack of clinical information provided and insufficient participation by informative family members. Although this substitution occurs at a position where amino acids with similar properties to glutamate are tolerated across species, E722K 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. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function.
Color Diagnostics, LLC DBA Color Health	RCV001179382	SCV001344036	uncertain significance	Cardiomyopathy	2022-11-09	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with lysine at codon 722 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 8/245704 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	RCV001248115	SCV001421580	uncertain significance	Hypertrophic cardiomyopathy	2022-07-12	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 722 of the MYBPC3 protein (p.Glu722Lys). This variant is present in population databases (rs730880696, gnomAD 0.01%). This missense change has been observed in individual(s) with clinical features of MYBPC3-related conditions (PMID: 21520333). ClinVar contains an entry for this variant (Variation ID: 181125). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C15"). 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.
Ambry Genetics	RCV002426774	SCV002729188	uncertain significance	Cardiovascular phenotype	2022-10-24	criteria provided, single submitter	clinical testing	The p.E722K variant (also known as c.2164G>A), located in coding exon 23 of the MYBPC3 gene, results from a G to A substitution at nucleotide position 2164. The glutamic acid at codon 722 is replaced by lysine, an amino acid with similar properties. 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.
All of Us Research Program, National Institutes of Health	RCV001248115	SCV004842386	uncertain significance	Hypertrophic cardiomyopathy	2024-03-24	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with lysine at codon 722 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 cardiovascular disorders in the literature. This variant has been identified in 8/245704 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.
Breakthrough Genomics, Breakthrough Genomics	RCV000158441	SCV005191285	uncertain significance	not provided		criteria provided, single submitter	not provided