Submissions for variant NM_000256.3(MYBPC3):c.3065G>C (p.Arg1022Pro)

gnomAD frequency: 0.00004  dbSNP: rs397516000

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000167911	SCV000059205	likely pathogenic	Hypertrophic cardiomyopathy	2019-08-16	criteria provided, single submitter	clinical testing	The p.Arg1022Pro variant has been reported in >15 heterozygous individuals with HCM (Bos 2014, Brito 2005, Brito 2012, Cecconi 2016, Hazebroek 2015, Lopes 2013, Mademont-Soler 2017, Millat 2010, Walsh 2016, van Velzen 2018, Montserrat 2011- pers. comm., LMM data), 1 compound heterozygous individual with HCM (Rodriguez-Garcia 2010), and 1 compound heterozygous individual with DCM (Hazebroek 2015). This variant segregated with disease in 3 affected individuals and was absent in 2 family members with borderline LVH in one family (Rodriguez-Garcia 2010). This variant has been reported in ClinVar (Variation ID: 42682) and has been seen in 0.005% (6/127826) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). Computational prediction tools and conservation analysis are consistent with pathogenicity. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant HCM. ACMG/AMP Criteria applied: PS4, PM2_Supporting, PP1, PP3.
GeneDx	RCV000035555	SCV000208146	uncertain significance	not provided	2021-04-15	criteria provided, single submitter	clinical testing	Identified in six individuals with HCM from two Spanish families, however, two relatives with suspected diagnoses of HCM did not harbor the R1022P variant (Rodriguez-Garcia et al., 2010); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 20624503, 27600940, 26383716, 22857948, 16335287, 20800588, 23396983, 24093860, 25351510, 27532257, 23782526, 24793961, 26743238, 20433692, 28771489, 29661763, 30847666, 32880476)
Invitae	RCV000167911	SCV000218559	likely pathogenic	Hypertrophic cardiomyopathy	2023-10-03	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 1022 of the MYBPC3 protein (p.Arg1022Pro). This variant is present in population databases (rs397516000, gnomAD 0.005%). This missense change has been observed in individuals with hypertrophic or dilated cardiomyopathy (PMID: 20433692, 22857948, 23396983, 24093860, 28771489, 30847666). ClinVar contains an entry for this variant (Variation ID: 42682). 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. This variant disrupts the p.Arg1022 amino acid residue in MYBPC3. Other variant(s) that disrupt this residue have been observed in individuals with MYBPC3-related conditions (PMID: 22765922, 28790153), which suggests that this may be a clinically significant amino acid residue. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Laboratory of Genetics and Molecular Cardiology, University of São Paulo	RCV000168808	SCV000256157	likely pathogenic	Hypertrophic cardiomyopathy 4		criteria provided, single submitter	clinical testing
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV000257925	SCV000747959	uncertain significance	Primary familial hypertrophic cardiomyopathy	2016-12-02	criteria provided, single submitter	clinical testing
Mendelics	RCV000168808	SCV001138290	uncertain significance	Hypertrophic cardiomyopathy 4	2019-05-28	criteria provided, single submitter	clinical testing
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	RCV001027700	SCV001190275	pathogenic	Left ventricular noncompaction 10	2019-07-25	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001189182	SCV001356417	uncertain significance	Cardiomyopathy	2023-03-09	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with proline at codon 1022 of the MYBPC3 protein. Computational prediction tools and conservation analyses suggest that this variant may have a deleterious impact on the protein function. To our knowledge, functional assays have not been performed for this variant. This variant has been reported in over ten individuals affected with hypertrophic cardiomyopathy (PMID: 20433692, 20624503, 20800588, 22857948, 23396983, 23782526, 24093860, 27532257, 28771489, 30847666, 31983221, 32841044, 32880476, 33495596, 33495597). This variant was observed together with pathogenic variants in different genes that could explain the observed phenotype (PMID: 20624503, 23782526; communication with an external laboratory). This variant has been reported in six affected individuals from two different families, but two possibly affected individuals did not carry this variant (PMID: 20433692). This variant has been identified in 7/278058 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 has been classified as a Variant of Uncertain Significance.
Ambry Genetics	RCV002444467	SCV002753834	uncertain significance	Cardiovascular phenotype	2023-05-17	criteria provided, single submitter	clinical testing	The p.R1022P variant (also known as c.3065G>C), located in coding exon 29 of the MYBPC3 gene, results from a G to C substitution at nucleotide position 3065. The arginine at codon 1022 is replaced by proline, an amino acid with dissimilar properties. This alteration was first reported to occur de novo in a Portuguese patient with hypertrophic cardiomyopathy (HCM); however, details were limited (Brito D et al. Rev Port Cardiol. 2005;24:1137-46). In one family, this alteration segregated with hypertrophy in some individuals, but was absent in two family members who were indicated as probably affected (Rodríguez-García MI et al. BMC Med Genet. 2010;11:67). Subsequently, the alteration has been detected in additional HCM cohorts; however, in several cases, clinical details were limited or not provided, and the alteration co-occurred with other variants in some instances (Millat G et al. Clin Chim Acta. 2010;411:1983-91; Brito D et al. Rev Port Cardiol, 2012;31:577-87; Lopes LR et al. J Med Genet. 2013;50:228-39; Marsiglia JD et al. Am Heart J. 2013;166:775-82; Núñez L et al. Circ J. 2013;77:2358-65; Cecconi M et al. Int J Mol Med. 2016;38:1111-24). 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 and conflicting at this time, the clinical significance of this alteration remains unclear.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001189182	SCV003838267	likely pathogenic	Cardiomyopathy	2022-06-02	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000167911	SCV004836667	uncertain significance	Hypertrophic cardiomyopathy	2024-02-05	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with proline at codon 1022 of the MYBPC3 protein. Computational prediction tools and conservation analyses suggest that this variant may have a deleterious impact on the protein function. To our knowledge, functional assays have not been performed for this variant. This variant has been reported in over ten individuals affected with hypertrophic cardiomyopathy (PMID: 20433692, 20624503, 20800588, 22857948, 23396983, 23782526, 24093860, 27532257, 28771489, 30847666, 31983221, 32841044, 32880476, 33495596, 33495597). This variant was observed together with pathogenic variants in different genes that could explain the observed phenotype (PMID: 20624503, 23782526; communication with an external laboratory). This variant has been reported in six affected individuals from two different families, but two possibly affected individuals did not carry this variant (PMID: 20433692). This variant has been identified in 7/278058 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 has been classified as a Variant of Uncertain Significance.