11-47342734-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PM1PP3_ModerateBS2

The NM_000256.3(MYBPC3):​c.1468G>A​(p.Gly490Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000343 in 1,613,830 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00022 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00036 ( 2 hom. )

Consequence

MYBPC3
NM_000256.3 missense

Scores

14
5
1

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:17B:1

Conservation

PhyloP100: 7.51
Variant links:
Genes affected
MYBPC3 (HGNC:7551): (myosin binding protein C3) MYBPC3 encodes the cardiac isoform of myosin-binding protein C. Myosin-binding protein C is a myosin-associated protein found in the cross-bridge-bearing zone (C region) of A bands in striated muscle. MYBPC3 is expressed exclusively in heart muscle and is a key regulator of cardiac contraction. Mutations in this gene are a frequent cause of familial hypertrophic cardiomyopathy. [provided by RefSeq, May 2022]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM1
In a domain Ig-like C2-type 3 (size 90) in uniprot entity MYPC3_HUMAN there are 33 pathogenic changes around while only 9 benign (79%) in NM_000256.3
PP3
MetaRNN computational evidence supports a deleterious effect, 0.937
BS2
High Homozygotes in GnomAdExome4 at 2 AD,AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
MYBPC3NM_000256.3 linkuse as main transcriptc.1468G>A p.Gly490Arg missense_variant 17/35 ENST00000545968.6 NP_000247.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
MYBPC3ENST00000545968.6 linkuse as main transcriptc.1468G>A p.Gly490Arg missense_variant 17/355 NM_000256.3 ENSP00000442795 P4Q14896-1
MYBPC3ENST00000399249.6 linkuse as main transcriptc.1468G>A p.Gly490Arg missense_variant 16/345 ENSP00000382193 A2
MYBPC3ENST00000544791.1 linkuse as main transcriptc.1468G>A p.Gly490Arg missense_variant, NMD_transcript_variant 17/275 ENSP00000444259

Frequencies

GnomAD3 genomes
AF:
0.000223
AC:
34
AN:
152244
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.000145
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.0000941
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000397
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000221
AC:
55
AN:
249060
Hom.:
0
AF XY:
0.000192
AC XY:
26
AN XY:
135108
show subpopulations
Gnomad AFR exome
AF:
0.0000646
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.000229
Gnomad FIN exome
AF:
0.000139
Gnomad NFE exome
AF:
0.000381
Gnomad OTH exome
AF:
0.000166
GnomAD4 exome
AF:
0.000355
AC:
519
AN:
1461586
Hom.:
2
Cov.:
31
AF XY:
0.000381
AC XY:
277
AN XY:
727084
show subpopulations
Gnomad4 AFR exome
AF:
0.0000597
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.000301
Gnomad4 FIN exome
AF:
0.000393
Gnomad4 NFE exome
AF:
0.000408
Gnomad4 OTH exome
AF:
0.000265
GnomAD4 genome
AF:
0.000223
AC:
34
AN:
152244
Hom.:
0
Cov.:
33
AF XY:
0.000242
AC XY:
18
AN XY:
74384
show subpopulations
Gnomad4 AFR
AF:
0.000145
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.0000941
Gnomad4 NFE
AF:
0.000397
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000324
Hom.:
0
Bravo
AF:
0.000185
ESP6500AA
AF:
0.000235
AC:
1
ESP6500EA
AF:
0.000354
AC:
3
ExAC
AF:
0.000206
AC:
25
EpiCase
AF:
0.000218
EpiControl
AF:
0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:2Uncertain:17Benign:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:4Benign:1
Uncertain significance, criteria provided, single submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesJun 30, 2020The MYBPC3 c.1468G>A; p.Gly490Arg variant (rs200625851) is reported in the literature and ClinVar (Variation ID: 42536) in patients affected with cardiomyopathy (Perkins 2018, Whiffin 2017, van Velzen 2017, Amendola 2015, Ng 2013). An alternative change (p.Gly490Val) has also been reported in homozygote siblings affected with hypertrophic cardiomyopathy (Wang 2013). Given the lack of robust segregation data and functional studies, the exact consequence of this variant is unknown. This variant is found in the non-Finnish European population with an allele frequency of 0.04% (46/128,326 alleles) in the Genome Aggregation Database. The glycine at codon 490 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Due to limited information, the clinical significance of the p.Gly490Arg variant is uncertain at this time. Gene statement: Pathogenic variants in MYBPC3 are inherited in an autosomal dominant manner, and are associated with dilated cardiomyopathy 1MM and left ventricular noncompaction 10 (MIM: 615396) and hypertrophic cardiomyopathy 4 (MIM: 115197). References: Perkins et al., Precision Medicine Screening Using Whole-Genome Sequencing and Advanced Imaging to Identify Disease Risk in Adults Proc Natl Acad Sci U S A. 2018 Apr 3;115(14):3686-3691 Whiffin et al., Using High-Resolution Variant Frequencies to Empower Clinical Genome Interpretation. Genet Med. 2017 Oct;19(10):1151-1158 van Velzen et al., Clinical Characteristics and Long-Term Outcome of Hypertrophic Cardiomyopathy in Individuals With a MYBPC3 (Myosin-Binding Protein C) Founder Mutation. Circ Cardiovasc Genet. 2017 Aug;10(4):e001660 Amendola et al., Actionable Exomic Incidental Findings in 6503 Participants: Challenges of Variant Classification. Genome Res. 2015 Mar;25(3):305-15 Ng et al. Interpreting Secondary Cardiac Disease Variants in an Exome Cohort. Circ Cardiovasc Genetcis 2013 Aug;6(4):337-46 Wang et al. Autosomal Recessive Transmission of MYBPC3 Mutation Results in Malignant Phenotype of Hypertrophic Cardiomyopathy. PLoS One 2013 Jun 28;8(6):e67087. -
Likely benign, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenOct 01, 2024MYBPC3: BS2 -
Uncertain significance, criteria provided, single submitterclinical testingGeneDxDec 21, 2024Reported numerous times in individuals with HCM, DCM, and/or LVNC referred for genetic testing at GeneDx and in published literature; however, multiple probands harbor additional cardiogenetic variants that likely contribute to their phenotype (PMID: 18403758, 15519027, 16754800, 20624503, 20215591, 21551322, 22267749, 23861362, 24503780, 26936621, 28794111, 30847666, 32880476, 35653365, 35200695); 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: 23299917, 25637381, 24055113, 16858239, 18533079, 22337857, 22267749, 23840593, 19293840, 20624503, 24510615, 20215591, 21551322, 15519027, 16754800, 26936621, 23861362, 25524337, 29555771, 28794111, 28518168, 31019283, 27066506, 24503780, 34426522, 30291343, 37652022, 31980526, 31737537, 30847666, 32880476, 35200695, 35653365, 18403758) -
Uncertain significance, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineApr 04, 2019The p.Gly490Arg variant in MYBPC3 has been reported in 14 individuals with a variety of cardiomyopathies (8 with HCM: Van Driest 2004, Girolami 2006, Olivotto 2008, Coppini 2014; 1 with increased left ventricular wall thickness: Morita 2006, LMM data; 2 with DCM: Hershberger 2010, LMM data; 1 with ARVC: LMM data; and 2 individuals with LVNC: Probst 2011), and segregated with LVNC in 1 relative (Probst 2011). At least three of these individuals carried a second variant sufficient to explain their disease. This variant has been reported in ClinVar (Variant ID: 42536). The p.Gly490Arg variant has also been identified in 21/66570 European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs200625851). The frequency of this variant in the general population raises concern as to whether it is disease causing. In summary, the clinical significance of the p.Gly490Arg variant is uncertain. -
Uncertain significance, criteria provided, single submitterclinical testingClinical Genetics Laboratory, Skane University Hospital LundOct 03, 2022- -
Hypertrophic cardiomyopathy Uncertain:3
Uncertain significance, criteria provided, single submitterclinical testingAll of Us Research Program, National Institutes of HealthAug 23, 2024This missense variant replaces glycine with arginine at codon 490 of the MYBPC3 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in multiple individuals affected with hypertrophic cardiomyopathy (PMID: 15519027, 16858239, 18403758, 22267749, 26936621, 33495596, 35200695), three individuals with left ventricular non-compaction in two families (PMID: 21551322), and one individual with dilated cardiomyopathy (PMID: 22337857). However, this variant co-occurred with MYBPC3 pathogenic variants in three individuals with hypertrophic cardiomyopathy (PMID: 22267749, 26936621), suggesting that this variant is unlikely responsible for the disease observed in these individuals. This variant has also been identified in 60/280454 chromosomes (46/128326 Non-Finnish European) 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. -
Uncertain significance, criteria provided, single submitterresearchBiesecker Lab/Clinical Genomics Section, National Institutes of HealthJan 04, 2017- -
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 31, 2024This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 490 of the MYBPC3 protein (p.Gly490Arg). This variant is present in population databases (rs200625851, gnomAD 0.04%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with clinical features of MYBPC3-related conditions (PMID: 1853307, 15519027, 16858239, 18403758, 20215591, 20624503, 21551322, 22267749, 28794111, 32880476). ClinVar contains an entry for this variant (Variation ID: 42536). 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. 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. -
Left ventricular noncompaction 10 Uncertain:2
Uncertain significance, criteria provided, single submitterclinical testingInstitute of Human Genetics, University of Leipzig Medical CenterJan 01, 2019- -
Uncertain significance, criteria provided, single submitterclinical testingEquipe Genetique des Anomalies du Developpement, Université de BourgogneNov 21, 2018- -
Cardiomyopathy Uncertain:2
Uncertain significance, criteria provided, single submitterclinical testingCHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern OntarioApr 04, 2023- -
Uncertain significance, criteria provided, single submitterclinical testingColor Diagnostics, LLC DBA Color HealthDec 16, 2022This missense variant replaces glycine with arginine at codon 490 of the MYBPC3 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in multiple individuals affected with hypertrophic cardiomyopathy (PMID: 15519027, 16858239, 18403758, 22267749, 26936621, 33495596, 35200695), three individuals with left ventricular non-compaction in two families (PMID: 21551322), and one individual with dilated cardiomyopathy (PMID: 22337857). However, this variant co-occurred with MYBPC3 pathogenic variants in three individuals with hypertrophic cardiomyopathy (PMID: 22267749, 26936621), suggesting that this variant is unlikely responsible for the disease observed in these individuals. This variant has also been identified in 60/280454 chromosomes (46/128326 Non-Finnish European) 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. -
Primary familial hypertrophic cardiomyopathy Uncertain:2
Uncertain significance, no assertion criteria providedresearchCSER _CC_NCGL, University of WashingtonJun 01, 2014- -
Uncertain significance, criteria provided, single submitterclinical testingBlueprint GeneticsMar 26, 2015- -
Cardiomyopathy, dilated, 1MM Pathogenic:1
Pathogenic, no assertion criteria providedliterature onlyOMIMAug 01, 2011- -
Hypertrophic cardiomyopathy 4 Pathogenic:1
Pathogenic, no assertion criteria providedliterature onlyOMIMAug 01, 2011- -
not specified Uncertain:1
Uncertain significance, no assertion criteria providedclinical testingStanford Center for Inherited Cardiovascular Disease, Stanford UniversityJul 20, 2014Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. MYBPC3 p.Gly490Arg In total, this variant has been reported in 14 unrelated patients with cardiomyopathy in the literature and available case data from two laboratories, in association with both HCM and DCM. However, at least 10 of these patients had other variants also identified that are considered more likely or sufficient to cause their disease (i.e. MYBPC3 frameshift variants). This variant is non-conservative, where a nonpolar glycine is exchanged for a positively charged polar arginine residue. The glycine at this residue is fully conserved across species, as are most neighboring amino acids. In silico analysis with PolyPhen predicts disease causing with a score of 0.997and mutation taster predicts disease causing. Van Driest et al. 2004 screened 389 unrelated patients with HCM for mutations in MYBPC3 at the Mayo Clinic. This cohort had been previously genotyped for mutations in MYH7, MYL2, MYL3, TNNT2, TNNI3, TPM1, and ACTC. Screened 200 controls. This Gly490Arg variant was identified in a single proband in this study and was absent from the 200 controls (100 of African American and 100 of Caucasian ancestry). No family history information or segregation data reported. Olivotto 2008: Screened 203 index patients with HCM of Italian descent. Screened patients for mutations in 8 sarcomeric genes. This variant was identified in the presence of another MYBPC3 missense variant (R502Q) in one patient. No screening for this variant in controls because it was not novel. Morita 2008: (Seidman team) Assessed 84 children with idiopathic cardiac hypertrophy on echocardiogram diagnosed before 15 years old for variants in 8 genes – MYH7, MYBPC3, TNNT2, TNNI3, TPM1, MYL3, MYL2, ACTC, PRKAG2, and LAMP2. Because this variant had been previously reported, they did not screen ethnicity-matched controls for this specific variant. Identified Gly490Arg in 1 child with idiopathic cardiac hypertrophy diagnosed before 15 yo. No family history or segregation information provided. Hershberger et al 2010 screened 312 patients with dilated cardiomyopathy (181 with familial DCM and 131 with idiopathic DCM) for disease-causing variants in MYBPC3, MYH6, TPM1, TNNC1, and TNNI3. This cohort had previously been sequenced for mutations in MYH7, TNNT2, SCN5A, CSRP3, LDB3, and TCAP. The cohort was comprised of mainly individuals of Caucasian descent (290/312). All variants were absent from 246 control samples of white, Yoruban, Asian and Hispanic ancestries. Gly490Arg was identified in one proband with familial DCM, and considered “possibly disease causing” because segregation with DCM could not be assessed. Probst et al 2011 screened 63 Caucasian probands with LVNC for mutations in 8 sarcomeric genes. Screened 180 control individuals. This variant was identified in two unrelated probands with LVNC in their cohort; one patient diagnosed with LVNC @ 70 who’s 32 yo affected son also carried the variant; and one patient with “sporadic” LVNC (meaning family members were not affected). This variant is present with an allele frequency of 0.035% in the European American cohort of the NHLBI Exome Sequencing project. It is currently present in ClinVar, HGMD and Harvard “ClinPath” databases as a pathogenic mutation, on the basis of the papers described above. In total, this variant has been seen in 4 of approximately 7,126 control individuals from publicly available datasets and controls in the published literature (Present in 4 of approximately 6500 individuals of African American and European American ancestry from the NHLBI ESP project; 200 controls from Van Driest et al. 2004; 246 controls from Hershberger 2010; and 180 controls from Probst et al. 2011 -
Hypertrophic cardiomyopathy 4;C3715165:Left ventricular noncompaction 10 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsApr 18, 2022- -
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsJul 28, 2023The p.G490R variant (also known as c.1468G>A), located in coding exon 17 of the MYBPC3 gene, results from a G to A substitution at nucleotide position 1468. The glycine at codon 490 is replaced by arginine, an amino acid with dissimilar properties. This variant has been reported in individuals with hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM), and left ventricular non-compaction (LVNC); however, in several cases, this variant was found in conjunction with other alterations in MYBPC3 and other cardiac-related genes (Van Driest SL et al. J Am Coll Cardiol. 2004;44:1903-10; Morita H et al. Circulation. 2006;113:2697-705; Olivotto I et al. Mayo Clin Proc. 2008;83:630-8; Hershberger RE et al. Circ Cardiovasc Genet. 2010;3:155-61; Probst S et al. Circ Cardiovasc Genet. 2011;4:367-74; Page SP et al. Circ Cardiovasc Genet. 2012;5:156-66; Coppini R et al. J Am Coll Cardiol. 2014;64:2589-600; Bales ND et al. Pediatr Cardiol. 2016;37:845-51). Internal structural analysis showed this variant is suggested to destabilize a hairpin turn motif in Ig-like domain C3 (Ambry Internal Data). 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. -
MYBPC3-related disorder Uncertain:1
Uncertain significance, no assertion criteria providedclinical testingPreventionGenetics, part of Exact SciencesJan 03, 2024The MYBPC3 c.1468G>A variant is predicted to result in the amino acid substitution p.Gly490Arg. This variant has been reported in individuals with MYBPC3-related phenotypes, including hypertrophic cardiomyopathy, dilated cardiomyopathy, and left ventricular noncompaction (Morita et al. 2006. PubMed ID: 16754800; Girolami et al. 2006. PubMed ID: 16858239; Probst et al. 2011. PubMed ID: 21551322; Norton et al. 2012. PubMed ID: 22337857; Bales et al. 2016. PubMed ID: 26936621). However, functional studies for this variant have not been reported and some individuals with this variant also had additional variants in MYBPC3 or other cardiomyopathy-related genes that are likely contributing to the phenotypes (Page et al. 2012. PubMed ID: 22267749; Bales et al. 2016. PubMed ID: 26936621). This variant is reported in 0.036% of alleles in individuals of European (Non-Finnish) descent in gnomAD and is interpreted as uncertain significance by most submitters in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/42536/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.58
CardioboostCm
Uncertain
0.41
BayesDel_addAF
Pathogenic
0.21
D
BayesDel_noAF
Pathogenic
0.38
CADD
Pathogenic
27
DANN
Pathogenic
1.0
DEOGEN2
Uncertain
0.78
D;T;T
Eigen
Pathogenic
0.86
Eigen_PC
Pathogenic
0.76
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Pathogenic
0.99
D;D;D
M_CAP
Pathogenic
0.70
D
MetaRNN
Pathogenic
0.94
D;D;D
MetaSVM
Pathogenic
0.83
D
MutationAssessor
Pathogenic
3.6
H;.;.
MutationTaster
Benign
1.0
D;D;D
PrimateAI
Uncertain
0.77
T
PROVEAN
Pathogenic
-6.7
D;.;D
REVEL
Pathogenic
0.90
Sift
Uncertain
0.0010
D;.;D
Sift4G
Uncertain
0.0030
D;D;D
Vest4
0.94
MVP
0.95
MPC
0.91
ClinPred
0.78
D
GERP RS
4.6
Varity_R
0.79
gMVP
0.82

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.10
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs200625851; hg19: chr11-47364285; API