chr11-47342719-G-C

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PM5PP3_ModeratePP5_Very_Strong

The NM_000256.3(MYBPC3):c.1483C>G(p.Arg495Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000112 in 1,613,880 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R495Q) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

MYBPC3
NM_000256.3 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:13

Conservation

PhyloP100: 2.76

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]

MYBPC3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 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

PM5

Other missense variant is known to change same aminoacid residue: Variant chr11-47342718-C-T is described in Lovd as [Pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.848

PP5

Variant 11-47342719-G-C is Pathogenic according to our data. Variant chr11-47342719-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 42537.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-47342719-G-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYBPC3	NM_000256.3 link	c.1483C>G	p.Arg495Gly	missense_variant	Exon 17 of 35	ENST00000545968.6	NP_000247.2	Q14896-1A5YM48

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
MYBPC3	ENST00000545968.6 link	c.1483C>G	p.Arg495Gly	missense_variant	Exon 17 of 35	5	NM_000256.3	ENSP00000442795.1	Q14896-1
MYBPC3	ENST00000399249.6 link	c.1483C>G	p.Arg495Gly	missense_variant	Exon 16 of 34	5		ENSP00000382193.2	A8MXZ9
MYBPC3	ENST00000544791.1 link	n.1483C>G		non_coding_transcript_exon_variant	Exon 17 of 27	5		ENSP00000444259.1	F5GZR4

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152202

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000401

AC:

AN:

249206

Hom.:

AF XY:

0.00000740

AC XY:

AN XY:

135206

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000885

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000116

AC:

AN:

1461678

Hom.:

Cov.:

AF XY:

0.00000963

AC XY:

AN XY:

727130

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000153

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152202

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74360

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hypertrophic cardiomyopathy

Pathogenic:4

Sep 12, 2024

All of Us Research Program, National Institutes of Health

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces arginine with glycine at codon 495 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 multiple individuals affected with hypertrophic cardiomyopathy (PMID: 18403758, 19659763, 20624503, 22267749, 23140321, 25611685, 26455666; www.cardiodb.org). This variant has also been observed in asymptomatic carriers, suggesting incomplete penetrance (PMID: 20019025). This variant has been identified in 1/249206 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Different missense substitutions at this codon, p.Arg495Gln and p.Arg495Trp, are reported to be pathogenic (Clinvar variation ID: 164113 and 164114, respectively), indicating the importance of arginine residue at this position. Based on the available evidence, this variant is classified as Likely Pathogenic. -

Feb 06, 2017

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Arg495Gly variant in MYBPC3 has been identified in 7 individuals with HCM (Morita 2008, Frisso 2009, Millat 2010, Calore 2015, LMM data), including 2 who also carried an additional disease-causing variant, and has also been reported b y other clinical laboratories in ClinVar (Variation ID: 42537). This variant seg regated with disease in 3 affected family members from 2 families (Frisso 2009, LMM data). However, this variant did not segregate with disease in all families (Morita 2008). It has been identified in 1/111690 European chromosomes by the Ex ome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs397515 905). In addition, two different amino acid changes at this position (p.Arg495Tr p and p.Arg495Gln) have been reported in individuals with HCM (Niimura 1998, Mar on 2001, Garcia-Castro 2009, Martin 2009, Rodriguez-Garcia 2010, Brito 2012, Cot o 2012, Lopes 2013), suggesting that changes at this position are not tolerated. However, data suggests that the p.Arg495Gln variant may have reduced penetrance . Computational prediction tools and conservation analysis suggest that this var iant may impact the protein. In summary, although additional studies are require d to fully establish its clinical significance, the p.Arg495Gly variant is likel y pathogenic. ACMG/AMP criteria applied (Richards 2015): PS4_Moderate, PM2, PP1, PP3. -

Zaffran Lab, Genetics of Cardiac Diseases Laboratory, Marseille Medical Genetics

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Oct 27, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 495 of the MYBPC3 protein (p.Arg495Gly). This variant is present in population databases (rs397515905, gnomAD 0.0009%). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 18403758, 19659763, 20624503, 22574137). ClinVar contains an entry for this variant (Variation ID: 42537). 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.Arg495 amino acid residue in MYBPC3. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9562578, 19150014, 20433692, 22765922, 23396983, 26671970). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Cardiomyopathy

Pathogenic:2

Jan 26, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces arginine with glycine at codon 495 in the Ig-like domain C3 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: 18403758, 19659763, 20624503, 22267749, 22574137, 23140321, 25611685, 26455666, 27532257, 28615295, 34310159). Different variants occurring at the same codon, p.Arg495Gln and p.Arg495Trp, are well documented pathogenic mutations (Clinvar variation ID: 164113 and 164114), indicating that arginine at this position is important for MYBPC3 protein function. This variant has been identified in 1/249206 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -

Feb 24, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: MYBPC3 c.1483C>G (p.Arg495Gly) results in a non-conservative amino acid change in the encoded protein sequence. Three of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 249206 control chromosomes. c.1483C>G has been reported in the literature in multiple individuals affected with Cardiomyopathy (e.g. Morita_2008, Frisso_2009, Millat_2010, Lopes_2013). These data indicate that the variant is very likely to be associated with disease. A different variant affecting the same codon has been classified as pathogenic by our lab (c.1484G>A, p.Arg495Gln), supporting the critical relevance of codon 495 to MYBPC3 protein function. The following publications have been ascertained in the context of this evaluation (PMID: 19659763, 23396983, 20624503, 18403758). ClinVar contains an entry for this variant (Variation ID: 42537). Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided

Pathogenic:2

Mar 17, 2022

Revvity Omics, Revvity

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 21, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 19659763, 22574137, 26671970, 31006259, 23140321, 23396983, 22267749, 18403758, 24704860, 20624503, 23690394, 20433692, 9562578, 18713777, 19150014, 11499718, 28615295, 25611685, 25740977, 25031304, 21415409, 25058872, 22857948, 22765922, 27532257, 28408708, 31447099, 31589614, 33012304, 33087929, 34400558, 20019025) -

Hypertrophic cardiomyopathy 4

Pathogenic:2

May 06, 2021

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.3, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with dilated cardiomyopathy, 1MM (MIM#615396), hypertrophic cardiomyopathy, 4 (MIM#115197) and left ventricular noncompaction 10 (MIM#615396). (I) 0108 - This gene is associated with both recessive and dominant disease. This gene is primarily associated with dominant disease but is also associated with autosomal recessive disease, mainly with malignant hypertrophic cardiomyopathy (OMIM). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to glycine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2) <0.001 for a dominant condition (1 heterozygote, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (6 heterozygotes, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated C3 Ig-like domain (PMID: 19659763). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported in multiple individuals with either childhood or adult-onset hypertrophic cardiomyopathy (ClinVar; PMIDs: 19659763, 18403758, 20624503, 25740977, 28615295, 28640247). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Dec 20, 2023

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Left ventricular noncompaction 10

Pathogenic:1

Dec 20, 2023

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiovascular phenotype

Pathogenic:1

Nov 07, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R495G pathogenic mutation (also known as c.1483C>G), located in coding exon 17 of the MYBPC3 gene, results from a C to G substitution at nucleotide position 1483. The arginine at codon 495 is replaced by glycine, an amino acid with dissimilar properties. This alteration has been detected in multiple individuals with features consistent with hypertrophic cardiomyopathy (HCM) (Morita HN et al. Engl J Med. 2008;358(18):1899-908; Millat G et al. Eur J Med Genet. 2010;53:261-7; Teirlinck CH et al. BMC Med Genet. 2012;13:105; Calore C et al. J Med Genet. 2015;52:338-47; Lopes LR et al. Heart. 2015;101(4):294-301; Walsh R et al. Genet. Med., 2017 Feb;19:192-203; Ross SB et al. Circ Cardiovasc Genet, 2017 Jun;10). This alteration has also been detected in individuals described as having HCM with non-compaction or dilated-phase HCM (Frisso G et al. Clin Genet. 2009;76(1):91-101; Page SP et al. Circ Cardiovasc Genet. 2012;5(2):156-66). Two other variants at the same codon, p.R495Q (c.1484G>A) and p.R495W (c.1483C>T), have also been reported in association with HCM (García-Castro M et al. Rev Esp Cardiol. 2009 Jan;62(1):48-56; Helms AS. Circ Cardiovasc Genet. 2014 Aug;7(4):434-43). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this variant is interpreted as a disease-causing mutation. -

Hypertrophic cardiomyopathy 1

Pathogenic:1

Mar 14, 2017

Agnes Ginges Centre for Molecular Cardiology, Centenary Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

This MYBPC3 Arg495Gly variant has previously been identified in multiple unrelated HCM cases and absent from >1500 control chromosomes, collectively (Alfares AA, et al., 2015; Morita H, et al., 2008; Frisso G, et al., 2009; Millat G, et al., 2010; Calore C, et al., 2015; Oxford genetics, https://cardiodb.org.uk/ACGV/acgv_variant.php?id=4185). This variant is also absent from the 1000 genomes project (http://www.1000genomes.org/), as well as the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/). Familial evaluation by Page SP, et al. (2012) identified Arg495Gly in 3 affected HCM cases (2 families) with fully penetrant disease. Similarly, Frisso G, et al. (2009) found the MYBPC3 Arg495Gly variant in 2 affected family members albeit with different disease phenotypes - one individual was diagnosed with childhood HCM, and his father with LVNC. Incomplete penetrance and/or asymptomatic carriers of this variant has been reported in the literature where familial screening is available (Christiaans I, et al., 2010; Morita H, et al., 2008). We identified this variant in 1 HCM proband with a family history of disease, however segregation was not possible. Interestingly, other amino acid substitutions at codon 495 (Arg495Trp, Arg495Gln) have also been idenitifed in HCM cases, and the Arg495Gln variant has been classified as a pathogenic variant, which provides strong support that that an amino acid substitution at this position is not tolerated. Structurally, Arg495 is located in a positively charged region of the C3 domain, where it is exposed on the protein surface of MYBPC3. It is predicted that amino acid substitutions in this domain will likely perturb the surface charge and disrupt the interaction of MYBPC3 with other proteins (Zhang XL, et al., 2014). In silico tools (SIFT, PolyPhen-2, MutationTaster) predict MYBPC3 Arg495Gly to be disease-causing. In summary, based on rarity in general populations, reports of multiple HCM probands with the variant, segregation data and the pathogenic classification of a different amino acid substitution at this position, we classify the MYBPC3 Arg495Gly variant as "pathogenic". -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

CardioboostCm

Uncertain

0.77

BayesDel_addAF

Pathogenic

0.27

BayesDel_noAF

Pathogenic

0.15

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.69

D;T;T

Eigen

Uncertain

0.33

Eigen_PC

Uncertain

0.31

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.93

D;D;D

M_CAP

Uncertain

0.25

MetaRNN

Pathogenic

0.85

D;D;D

MetaSVM

Benign

-0.40

MutationAssessor

Benign

2.0

M;.;.

PrimateAI

Uncertain

0.67

PROVEAN

Uncertain

-4.3

D;.;D

REVEL

Uncertain

0.50

Sift

Benign

0.047

D;.;D

Sift4G

Uncertain

0.042

D;D;D

Vest4

0.94

MVP

0.84

MPC

0.94

ClinPred

0.97

GERP RS

3.7

Varity_R

0.36

gMVP

0.77

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over