ClinVar Miner

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

gnomAD frequency: 0.00002  dbSNP: rs2856655
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Total submissions: 16
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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 2024-12-30 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, 36264615, 33673806, 33407484, 34135346, 33658040, 34542152, 34915024, 32492895, 34400558, 32830170, 22267749, 12628722, 18533079, 37652022)
Labcorp Genetics (formerly Invitae), Labcorp 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 2024-07-15 criteria provided, single submitter clinical testing The p.R820Q variant (also known as c.2459G>A), located in coding exon 25 of the MYBPC3 gene, results from a G to A substitution at nucleotide position 2459. The arginine at codon 820 is replaced by glutamine, an amino acid with highly similar properties. This alteration has been reported in multiple individuals with hypertrophic cardiomyopathy (HCM), and has been shown to segregate with disease (Konno T et al. J. Am. Coll. Cardiol., 2003 Mar;41:781-6; Nanni L et al. Biochem. Biophys. Res. Commun., 2003 Sep;309:391-8; Bahrudin U et al. J. Mol. Biol., 2008 Dec;384:896-907; Otsuka H et al. Circ. J., 2012 Nov;76:453-61; Lopes LR et al. Heart, 2015 Feb;101:294-301; Seidelmann SB et al. Circ Cardiovasc Genet, 2017 Feb;10; Walsh R et al. Genet. Med., 2017 Feb;19:192-203). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be 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 2024-09-16 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 tools indicate that this variant has a neutral impact on protein structure and function. A functional study performed in a zebrafish model has shown that this variant causes a phenotype consistent with hypertrophic cardiomyopathy (PMID: 25281569). This variant has been reported in over 30 unrelated individuals affected with hypertrophic cardiomyopathy (PMID: 12628722, 14563344, 16181148, 22112859, 22267749, 24510615, 25351510, 27483260, 27532257, 28087566, 32492895, 32830170, 32841044, 33407484, 33487615, 33495596, 33495597, 33658040, 33673806, 33782553, 34542152, 38489124, 38757491). It has been shown that this variant segregates with disease in six affected individuals across three 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 two 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.
OMIM RCV000009148 SCV000029365 pathogenic Hypertrophic cardiomyopathy 4 2005-02-01 no assertion criteria provided literature only
PreventionGenetics, part of Exact Sciences RCV004739298 SCV005363055 likely pathogenic MYBPC3-related disorder 2024-03-14 no assertion criteria provided clinical testing The MYBPC3 c.2459G>A variant is predicted to result in the amino acid substitution p.Arg820Gln. This variant has been reported in the heterozygous state in individuals with hypertrophic cardiomyopathy and segregated with disease in multiple families (see, for example, Konno et al. 2003. PubMed ID: 12628722; Kim et al. 2020. PubMed ID: 32492895; Supplemental Table 2, Field et al. 2022. PubMed ID: 34400558), although it has been detected in the heterozygous state in asymptomatic carriers as well (Konno et al. 2003. PubMed ID: 12628722; Hayashi et al. 2018. PubMed ID: 29907873). It has also been described in the compound heterozygous state with a second MYBPC3 variant in one individual, who was noted to have substantial left ventricular hypertrophy at age 11 (Hodatsu et al. 2014. PubMed ID: 25281569). In vitro and in vivo experimental studies suggest this variant may affect protein function through impaired protein stability or protein-protein interactions within the sarcomere (Hodatsu et al. 2014. PubMed ID: 25281569; Nadvi et al. 2015. PubMed ID: 26688216; Pearce et al. 2024. PubMed ID: 38042491). Alternative nucleotide changes affecting the same amino acid (p.Arg820Trp, p.Arg820Pro) have been reported in individuals with hypertrophic cardiomyopathy (Ripoll Vera et al 2010. PubMed ID: 20542340; Supplementary Table S2, Sepp et al. 2022. PubMed ID: 35626289 ). This variant is reported in 0.0056% of alleles in individuals of East Asian descent in gnomAD. This variant is interpreted as likely pathogenic.

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