Submissions for variant NM_000256.3(MYBPC3):c.2459G>A (p.Arg820Gln)

gnomAD frequency: 0.00002  dbSNP: rs2856655

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000525220	SCV000198854	likely pathogenic	Hypertrophic cardiomyopathy	2022-11-03	criteria provided, single submitter	clinical testing	The p.Arg820Gln variant in MYBPC3 has been reported in 16 individuals with HCM, segregated with disease in 6 affected relatives from 3 families (Konno 2003 PMID: 12628722, Nanni 2003 PMID: 12951062, Alders 2003 PMID: 14563344, Shimizu 2003 PMID: 15671604, Konno 2006 PMID: 16181148, Kapplinger 2014 PMID: 24510615, and Hodatsu 2014 PMID: 25281569, LMM data), and has also been reported in ClinVar (Variation ID 8617). Additionally, it has been identified in 3/111676 of European chromosomes and 1/17248 of East Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs2856655). Animal models (zebrafish) support that this variant causes HCM (Hodatsu et al. 2014 PMID: 25281569). In summary, this variant meets criteria to be classified as likely pathogenic for hypertrophic cardiomyopathy in an autosomal dominant manner. ACMG/AMP Criteria Applied: PS4, PM2_Supporting, PS3_Moderate, PP1_Moderate.
GeneDx	RCV000158159	SCV000208094	likely pathogenic	not provided	2023-06-27	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); 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: 18761664, 23197398, 16181148, 31524317, 23396983, 26688216, 24510615, 12951062, 15671604, 25281569, 27483260, 27532257, 28420666, 29398688, 20975235, 17263690, 22112859, 19149795, 16115294, 24793961, 18929575, 20800588, 28087566, 25351510, 24621997, 20474083, 28679633, 29907873, 30165862, 31451005, 30847666, 31447099, 31142139, 33487615, 33673806, 33407484, 34135346, 33658040, 34542152, 34915024, 32492895, 34400558, 32830170, 12628722, 22267749, 18533079)
Invitae	RCV000525220	SCV000623557	pathogenic	Hypertrophic cardiomyopathy	2023-12-04	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 820 of the MYBPC3 protein (p.Arg820Gln). This variant is present in population databases (rs2856655, gnomAD 0.006%). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 12628722, 12951062, 18761664, 18929575, 20542340, 20800588, 22112859, 22267749, 25281569, 27483260, 28087566). It is commonly reported in individuals of Japan ancestry (PMID: 12628722, 12951062, 18761664, 18929575, 20542340, 20800588, 22112859, 22267749, 25281569, 27483260, 28087566). This variant is also known as c.2491G>A. ClinVar contains an entry for this variant (Variation ID: 8617). 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. Experimental studies have shown that this missense change affects MYBPC3 function (PMID: 25281569). For these reasons, this variant has been classified as Pathogenic.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001170416	SCV001332994	likely pathogenic	Cardiomyopathy	2018-02-05	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000158159	SCV002017838	likely pathogenic	not provided	2021-10-29	criteria provided, single submitter	clinical testing
3billion	RCV000009148	SCV002058165	likely pathogenic	Hypertrophic cardiomyopathy 4	2022-01-03	criteria provided, single submitter	clinical testing	The variant has been observed in multiple (>3) similarly affected unrelated individuals(PMID: 12628722, 12951062, PS4_S). Functional studies provide moderate evidence of the variant having a damaging effect on the gene or gene product(PMID: 25281569, PS3_M). The variant was co-segregated with Cardiomyopathy, hypertrophic, 4 in multiple affected family members (PMID: 12628722, 12951062, PP1_P). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000020, PM2_M). A different missense change at the same codon has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000195850, PMID:20542340, PM5_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
AiLife Diagnostics, AiLife Diagnostics	RCV000158159	SCV002503554	pathogenic	not provided	2021-08-03	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002453253	SCV002738189	likely pathogenic	Cardiovascular phenotype	2022-10-07	criteria provided, single submitter	clinical testing	The c.2459G>A (p.R820Q) alteration is located in exon 25 (coding exon 25) of the MYBPC3 gene. This alteration results from a G to A substitution at nucleotide position 2459, causing the arginine (R) at amino acid position 820 to be replaced by a glutamine (Q). Based on data from gnomAD, the T allele has an overall frequency of 0.002% (5/249220) total alleles studied. The highest observed frequency was 0.0056% (1/17976) of East Asian alleles. This alteration has been reported in multiple subjects with hypertrophic cardiomyopathy (HCM) and has been shown to segregate with disease (Konno, 2003; Nanni, 2003; Bahrudin, 2008; Otsuka, 2012; Lopes, 2015; Seidelmann, 2017; Walsh, 2017). This amino acid position is highly conserved in available vertebrate species. The in silico prediction for this alteration is inconclusive. Based on the available evidence, this alteration is classified as likely pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV002490343	SCV002798818	pathogenic	Hypertrophic cardiomyopathy 4; Left ventricular noncompaction 10	2021-10-16	criteria provided, single submitter	clinical testing
Clinical Center for Gene Diagnosis and Therapy, Department of Cardiovascular Surgery, The Second Xiangya Hospital of Central South University	RCV003319161	SCV003932407	pathogenic	Primary familial hypertrophic cardiomyopathy	2023-06-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003319161	SCV004030124	pathogenic	Primary familial hypertrophic cardiomyopathy	2023-07-10	criteria provided, single submitter	clinical testing	Variant summary: MYBPC3 c.2459G>A (p.Arg820Gln) results in a conservative amino acid change located in the fibronectin type III domain (IPR003961) of the encoded protein sequence. Two of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 249220 control chromosomes (gnomAD). c.2459G>A has been reported in the literature in multiple individuals and several families affected with Hypertrophic Cardiomyopathy, many of East Asian ancestry (e.g. Konno_2003, Hodatsu_2014, Chung_2020). These data indicate that the variant is very likely to be associated with disease. A publication reporting experimental evidence evaluating an impact on protein function in a zebrafish model suggests the variant may result in a more severe cardiac phenotype when together with p.Val762Asp in comparison to p.Val762Asp alone; however, since p.Arg820Gln was not examined alone, this study does not necessarily allow convincing conclusions about the variant effect (Hodatsu_2014). The following publications have been ascertained in the context of this evaluation (PMID: 32380161, 25281569, 12628722). Nine submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV001170416	SCV004358673	likely pathogenic	Cardiomyopathy	2023-06-20	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glutamine at codon 820 of the fibronectin type 3 domain C6 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). Functional studies in zebrafish have shown a phenotype consistent with hypertrophic cardiomyopathy (PMID: 25281569). This variant has been reported in over 20 unrelated individuals affected with hypertrophic cardiomyopathy (PMID: 12628722, 12951062, 14563344, 16181148, 22112859, 22267749, 24510615, 25351510, 27483260, 27532257, 28087566, 32492895, 32830170, 32841044, 33407484, 33487615, 33495596, 33495597, 33658040, 33673806, 33782553). It has been shown that this variant segregates with disease in 6 affected individuals across 3 families (PMID: 12628722). This variant has been reported in an individual affected with pediatric hypertrophic cardiomyopathy in compound heterozygous state with a different MYBPC3 variant (PMID: 25281569). This variant has also been reported in 2 individuals affected with dilated cardiomyopathy (PMID: 12628722, 15671604, 31524317). A different variant affecting the same codon, p.Arg820Trp, is considered to be disease-causing (ClinVar variation ID: 195850), suggesting that arginine at this position is important for MYBPC3 protein function. This variant has been identified in 5/249220 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	RCV000009148	SCV004807189	pathogenic	Hypertrophic cardiomyopathy 4	2024-03-26	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000525220	SCV004820643	likely pathogenic	Hypertrophic cardiomyopathy	2024-01-05	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glutamine at codon 820 of the fibronectin type 3 domain C6 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). Functional studies in zebrafish have shown a phenotype consistent with hypertrophic cardiomyopathy (PMID: 25281569). This variant has been reported in over 20 unrelated individuals affected with hypertrophic cardiomyopathy (PMID: 12628722, 12951062, 14563344, 16181148, 22112859, 22267749, 24510615, 25351510, 27483260, 27532257, 28087566, 32492895). It has been shown that this variant segregates with disease in 6 affected individuals across 3 families (PMID: 12628722). This variant has been reported in an individual affected with pediatric hypertrophic cardiomyopathy in compound heterozygous state with a different MYBPC3 variant (PMID: 25281569). This variant has also been reported in 2 individuals affected with dilated cardiomyopathy (PMID: 12628722, 15671604, 31524317). A different variant occurring at the same codon, p.Arg820Trp, is a likely pathogenic mutation (Clinvar variation ID: 195850), indicating that arginine at this position is important for MYBPC3 protein function. This variant has been identified in 5/249220 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.
OMIM	RCV000009148	SCV000029365	pathogenic	Hypertrophic cardiomyopathy 4	2005-02-01	no assertion criteria provided	literature only