rs775404728

Positions:

Variant summary

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

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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R820Q) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

MYBPC3
NM_000256.3 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9U: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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PM1

In a domain Fibronectin type-III 1 (size 96) in uniprot entity MYPC3_HUMAN there are 31 pathogenic changes around while only 3 benign (91%) in NM_000256.3

PM5

Other missense variant is known to change same aminoacid residue: Variant chr11-47337534-C-T is described in Lovd as [Pathogenic].

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 [Likely_pathogenic]. Clinvar id is 195850.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-47337535-G-A is described in Lovd as [Likely_pathogenic]. Variant chr11-47337535-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYBPC3	NM_000256.3 linkuse as main transcript	c.2458C>T	p.Arg820Trp	missense_variant	25/35	ENST00000545968.6	NP_000247.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYBPC3	ENST00000545968.6 linkuse as main transcript	c.2458C>T	p.Arg820Trp	missense_variant	25/35	5	NM_000256.3	ENSP00000442795	P4	Q14896-1
MYBPC3	ENST00000399249.6 linkuse as main transcript	c.2458C>T	p.Arg820Trp	missense_variant	24/34	5		ENSP00000382193	A2
MYBPC3	ENST00000544791.1 linkuse as main transcript	c.2414-24C>T		intron_variant, NMD_transcript_variant		5		ENSP00000444259

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000401

AC:

AN:

249210

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135184

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 SAS 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

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

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:

0.00000450

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ExAC

AF:

0.00000825

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hypertrophic cardiomyopathy 4

Pathogenic:4

Likely pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 08, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Apr 04, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Breakthrough Genomics, Breakthrough Genomics	Jul 12, 2020	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]. -

not provided

Pathogenic:2Uncertain:2

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 04, 2019	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) -
Uncertain significance, flagged submission	clinical testing	Eurofins Ntd Llc (ga)	May 04, 2015	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Uncertain significance, flagged submission	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jun 17, 2019	- -

Cardiomyopathy

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

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

Sep 03, 2021

- -

Hypertrophic cardiomyopathy

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 04, 2023

This missense change has been observed in individuals with hypertrophic cardiomyopathy and/or left ventricular noncompaction (PMID: 20542340, 28771489, 33782553; Invitae). 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 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). ClinVar contains an entry for this variant (Variation ID: 195850). For these reasons, this variant has been classified as Pathogenic. 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. Experimental studies have shown that this missense change affects MYBPC3 function (PMID: 17521870, 24906243, 26776584). 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. -

Cardiovascular phenotype

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 21, 2023

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

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;.;.

MutationTaster

Benign

1.0

D;D;D

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

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

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