rs775404728

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 7P and 1B. PM1PM5PP3_ModeratePP5BS2_Supporting

The NM_000256.3(MYBPC3):c.2458C>T(p.Arg820Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000041 in 1,461,686 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R820P) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

MYBPC3
NM_000256.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:10U:2

Conservation

PhyloP100: 1.47

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:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PM1

In a domain Fibronectin type-III 1 (size 96) in uniprot entity MYPC3_HUMAN there are 51 pathogenic changes around while only 6 benign (89%) in NM_000256.3

PM5

Other missense variant is known to change same aminoacid residue: Variant chr11-47337534-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 8617.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.872

PP5

Variant 11-47337535-G-A is Pathogenic according to our data. Variant chr11-47337535-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 195850.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=4, Uncertain_significance=2, Likely_pathogenic=4}. Variant chr11-47337535-G-A is described in Lovd as [Likely_pathogenic]. Variant chr11-47337535-G-A is described in Lovd as [Pathogenic].

BS2

High AC in GnomAdExome4 at 6 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYBPC3	NM_000256.3 link	c.2458C>T	p.Arg820Trp	missense_variant	Exon 25 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.2458C>T	p.Arg820Trp	missense_variant	Exon 25 of 35	5	NM_000256.3	ENSP00000442795.1	Q14896-1
MYBPC3	ENST00000399249.6 link	c.2458C>T	p.Arg820Trp	missense_variant	Exon 24 of 34	5		ENSP00000382193.2	A8MXZ9
MYBPC3	ENST00000544791.1 link	n.2414-24C>T		intron_variant	Intron 24 of 26	5		ENSP00000444259.1	F5GZR4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000401

AC:

AN:

249210

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000410

AC:

AN:

1461686

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727124

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.0000224

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53388

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000450

AC:

AN:

1111864

Other (OTH)

AF:

0.00

AC:

AN:

60374

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.00000825

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:10Uncertain:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hypertrophic cardiomyopathy 4

Pathogenic:4

Oct 08, 2014

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 12, 2020

Breakthrough Genomics, Breakthrough Genomics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant has been reported in the homozygous state in two related individuals affected with hypertrophic cardiomyopathy and left ventricular non-compaction; however, heterozygous carriers in this family were unaffected [PMID: 20542340]. Experimental studies have shown that felines with an equivalent variant develop hypertrophic cardiomyopathy [PMID: 17521870], however the clinical significance of this observation is uncertain. Another missense substitution at the same codon (p.Arg820Gln) has been reported as pathogenic [PMID: 12628722, 22112859, 22267749]. -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Apr 04, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Pathogenic:2Uncertain:2

Dec 04, 2019

GeneDx

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Reported in ClinVar (ClinVar Variant ID# 195850; Landrum et al., 2016); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 30284024, 19566849, 26776581, 28868097, 21147473, 26776585, 25622655, 26776584, 27076529, 26776595, 24602043, 21051304, 24906243, 23323744, 17521870, 21415409, 24447051, 29907873, 19035361, 29636697, 28642712, 28679633, 28771489, 20542340) -

May 04, 2015

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jun 17, 2019

Mayo Clinic Laboratories, Mayo Clinic

Significance:Uncertain significance

Review Status:flagged submission

Collection Method:clinical testing

- -

Cardiomyopathy

Pathogenic:2

Nov 21, 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 tryptophan at codon 820 in the fibronectin type 3 domain C6 of the MYBPC3 protein. Computational prediction tools indicate that this variant's impact on protein structure and function is inconclusive. A functional study using a transgenic Drosophila model showed that this variant produced a phenotype consistent with hypertrophic cardiomyopathy (PMID: 33561224). This variant has been observed in both heterozygous and homozygous state in ragdoll cats affected with hypertrophic cardiomyopathy (PMID: 17521870); the clinical relevance of this observation is not known. This variant has been reported in the heterozygous state in at least 8 unrelated individuals affected with hypertrophic cardiomyopathy (PMID: 28771489, 33407484, 33782553, 34310159; ClinVar SCV000546424.8, SCV002738183.1). It has also been reported in the homozygous state in 2 individuals from one family affected with hypertrophic cardiomyopathy (PMID: 20542340) and in one individual affected with left ventricular noncompaction cardiomyopathy (PMID: 33386538). A different variant occurring at the same codon, p.Arg820Gln, is considered to be disease-causing (Clinvar variation ID: 8617), suggesting that arginine at this position is important for MYBPC3 protein function. This variant has been identified in 1/249210 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -

Sep 03, 2021

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hypertrophic cardiomyopathy

Pathogenic:1

Jul 15, 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 tryptophan, which is neutral and slightly polar, at codon 820 of the MYBPC3 protein (p.Arg820Trp). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individuals with hypertrophic cardiomyopathy and/or left ventricular noncompaction (PMID: 20542340, 28771489, 33782553; Invitae). ClinVar contains an entry for this variant (Variation ID: 195850). 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: 17521870, 24906243, 26776584). This variant disrupts the p.Arg820 amino acid residue in MYBPC3. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12628722, 22112859, 22267749, 25281569). 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. -

Cardiovascular phenotype

Pathogenic:1

Nov 21, 2023

Ambry Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.R820W variant (also known as c.2458C>T), located in coding exon 25 of the MYBPC3 gene, results from a C to T substitution at nucleotide position 2458. The arginine at codon 820 is replaced by tryptophan, an amino acid with dissimilar properties. This alteration has been reported in the heterozygous and homozygous states in individuals with hypertrophic cardiomyopathy (HCM); however, heterozygous relatives of the homozygous proband were reportedly unaffected (Ripoll Vera T et al, Int. J. Cardiol. 2010 Nov; 145(2):405-7; Mademont-Soler I et al. PLoS ONE, 2017 Aug;12:e0181465; Chung H et al. Cardiovasc Ultrasound, 2021 Jan;19:4; Stava TT et al. Eur J Prev Cardiol. 2022 Oct;29(13):1789-1799; Ambry internal data). The same alteration (p.R820W) has also been detected in ragdoll cats exhibiting HCM (Meurs KM et al. Genomics, 2007 Aug;90:261-4). Another alteration at the same codon, p.R820Q (c.2459G>A), has been detected in individuals with HCM (Konno T et al. J. Am. Coll. Cardiol., 2003 Mar;41:781-6). 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.81

CardioboostCm

Uncertain

0.90

BayesDel_addAF

Pathogenic

0.30

BayesDel_noAF

Pathogenic

0.20

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.45

T;T;T

Eigen

Uncertain

0.59

Eigen_PC

Uncertain

0.45

FATHMM_MKL

Uncertain

0.76

LIST_S2

Pathogenic

0.99

D;D;D

M_CAP

Pathogenic

0.32

MetaRNN

Pathogenic

0.87

D;D;D

MetaSVM

Uncertain

0.013

MutationAssessor

Pathogenic

3.7

H;.;.

PhyloP100

1.5

PrimateAI

Uncertain

0.79

PROVEAN

Pathogenic

-6.5

D;.;D

REVEL

Pathogenic

0.65

Sift

Pathogenic

0.0

D;.;D

Sift4G

Pathogenic

0.0010

D;D;D

Vest4

0.95

MVP

0.86

MPC

0.85

ClinPred

0.99

GERP RS

2.5

Varity_R

0.72

gMVP

0.75

Mutation Taster

=5/95

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.17

Details are displayed if max score is > 0.2

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

Publications

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rs775404728

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over