Submissions for variant NM_000256.3(MYBPC3):c.1831G>A (p.Glu611Lys)

gnomAD frequency: 0.00005  dbSNP: rs730880555

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000244596	SCV000317936	uncertain significance	Cardiovascular phenotype	2023-08-03	criteria provided, single submitter	clinical testing	The p.E611K variant (also known as c.1831G>A), located in coding exon 19 of the MYBPC3 gene, results from a G to A substitution at nucleotide position 1831. The glutamic acid at codon 611 is replaced by lysine, an amino acid with similar properties. This alteration has been reported in multiple hypertrophic cardiomyopathy cohorts, a dilated cardiomyopathy cohort, and a noncompaction cardiomyopathy cohort; however, clinical details were limited and several had additional cardiac variants reported, including at least one patient who was also heterozygous for a pathogenic MYBPC3 alteration (Waldmüller S et al. Eur. J. Heart Fail., 2011 Nov;13:1185-92; Miller EM et al. J Genet Couns, 2013 Apr;22:258-67; Zou Y et al. Mol. Biol. Rep., 2013 Jun;40:3969-76; Berge KE et al. Clin. Genet., 2014 Oct;86:355-60; Ho CY et al. Circulation, 2018 Oct;138:1387-1398; van Waning JI et al. J. Am. Coll. Cardiol., 2018 Feb;71:711-722; van Lint FHM et al. Neth Heart J, 2019 Jun;27:304-309; Robyns T et al. Eur J Med Genet, 2020 Mar;63:103754; Nijenkamp LLAM et al. PLoS One, 2020 May;15:e0232427). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000244596	SCV000696320	likely pathogenic	Cardiovascular phenotype	2016-08-02	criteria provided, single submitter	clinical testing	Variant summary: The MYBPC3 c.1831G>A (p.Glu611Lys) variant involves the alteration of a conserved nucleotide. 3/4 in silico tools predict a damaging outcome for this variant (SNPs&GO not captured due to low reliability index). This variant is located in the Immunoglobulin I domain (InterPro). Other missense variants around this region have also been reported in HCM patients, such as p.Tyr614Cys, p.Asp610Val, p.Asp610His, p.Asp610Asn, p.Ala609Val, etc., suggesting a notion that the region is important for protein function; however they have conflicting interpretations of pathogenicity ranging from pathogenic to uncertain significance in ClinVar. This variant is absent in 52198 control chromosomes but has been reported in at least nine patients (2 DCM, 7 HCM) from multiple countries. However, there are no co-segregation studies in literature, nor are functional studies. One DCM patient was not comprehensively genotyped (Waldmuller_2014) while another DCM patient also has unspecified mutation(s) (Wang_2014). Thus, it may be possible that it is HCM-specific mutation. This variant was also found in one HCM patient who also carried another frameshift mutation in the same gene; however, phenotypic severity of the patient is not specified. One clinical lab has classified it as pathogenic. Taken together, this variant is classified as Probable Disease Variant (or Likely Pathogenic).
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000615268	SCV000731277	uncertain significance	not specified	2019-02-07	criteria provided, single submitter	clinical testing	The p.Glu611Lys variant in MYBPC3 has been reported in 2 individuals with HCM (Miller 2013, Zou 2013), in 1 individual with DCM (Waldmuller 2011) and in 1 individual with non compaction cardiomyopathy (Waning 2018). Of note, one of these individuals with HCM also carried a pathogenic variant in MYBPC3 (Miller 2013). It is present in CLinVar (ID 180955) (conflicting interpretations). The p.Glu611Lys variant was also identified in 1/27268 of South Asian chromosomes in gnomAD. Computational prediction tools and conservation analysis suggest that the p.Glu611Lys variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, the clinical significance of the p.Glu611Lys variant is uncertain.
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000600155	SCV000743558	likely pathogenic	Hypertrophic cardiomyopathy 4	2014-10-09	criteria provided, single submitter	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000600155	SCV000744847	pathogenic	Hypertrophic cardiomyopathy 4	2015-09-21	criteria provided, single submitter	clinical testing
Invitae	RCV000695616	SCV000824127	uncertain significance	Hypertrophic cardiomyopathy	2022-12-25	criteria provided, single submitter	clinical testing	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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 180955). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy, dilated cardiomyopathy, or noncompaction cardiomyopathy (PMID: 21750094, 23054336, 23283745, 24111713, 29447731, 30847666, 31513939). This variant is present in population databases (rs730880555, gnomAD 0.004%). This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 611 of the MYBPC3 protein (p.Glu611Lys).
Center for Human Genetics, University of Leuven	RCV000695616	SCV000886822	uncertain significance	Hypertrophic cardiomyopathy	2018-10-31	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000769326	SCV000900704	likely pathogenic	Cardiomyopathy	2023-05-16	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000769326	SCV001357701	uncertain significance	Cardiomyopathy	2023-02-02	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with lysine at codon 611 of the MYBPC3 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, 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: PMID: 23054336, 23283745, 24111713, 28971120, 30297972, 30847666, 31513939, 32369506). One of these individuals also carried a different pathogenic variant in the MYBPC3 gene (PMID: 23054336). It has also been reported in an individual affected with dilated cardiomyopathy (PMID: 21750094), an individual affected with noncompaction cardiomyopathy (PMID: 29447731), and in an individual affected with an unspecified cardiomyopathy (PMID: 30847666). This variant has been identified in 6/255294 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.
CeGaT Center for Human Genetics Tuebingen	RCV001706060	SCV002497118	uncertain significance	not provided	2022-02-01	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000695616	SCV004842429	uncertain significance	Hypertrophic cardiomyopathy	2023-12-01	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with lysine at codon 611 of the MYBPC3 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, 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: PMID: 23054336, 23283745, 24111713, 28971120, 30297972, 30847666, 31513939, 32369506). One of these individuals also carried a different pathogenic variant in the MYBPC3 gene (PMID: 23054336). It has also been reported in an individual affected with dilated cardiomyopathy (PMID: 21750094), an individual affected with noncompaction cardiomyopathy (PMID: 29447731), and in an individual affected with an unspecified cardiomyopathy (PMID: 30847666). This variant has been identified in 6/255294 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.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000600155	SCV000733045	pathogenic	Hypertrophic cardiomyopathy 4		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV001706060	SCV001921022	pathogenic	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV001706060	SCV001930797	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001706060	SCV001953624	pathogenic	not provided		no assertion criteria provided	clinical testing