rs397515956

Positions:

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1PM5BP4_Moderate

The NM_000256.3(MYBPC3):c.2197C>T(p.Arg733Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000855 in 1,613,858 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R733H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000088 ( 1 hom. )

Consequence

MYBPC3
NM_000256.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:11

Conservation

PhyloP100: 4.66

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 Uncertain_significance. Variant got 2 ACMG points.

PM1

In a strand (size 4) in uniprot entity MYPC3_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_000256.3

PM5

Other missense variant is known to change same aminoacid residue: Variant chr11-47338630-C-T is described in Lovd as [Pathogenic].

BP4

Computational evidence support a benign effect (MetaRNN=0.18215308).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYBPC3	NM_000256.3 linkuse as main transcript	c.2197C>T	p.Arg733Cys	missense_variant	23/35	ENST00000545968.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYBPC3	ENST00000545968.6 linkuse as main transcript	c.2197C>T	p.Arg733Cys	missense_variant	23/35	5	NM_000256.3	P4	Q14896-1
MYBPC3	ENST00000399249.6 linkuse as main transcript	c.2197C>T	p.Arg733Cys	missense_variant	22/34	5		A2
MYBPC3	ENST00000544791.1 linkuse as main transcript	c.2197C>T	p.Arg733Cys	missense_variant, NMD_transcript_variant	23/27	5

Frequencies

GnomAD3 genomes

AF:

0.0000657

AC:

AN:

152134

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000882

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000603

AC:

AN:

248658

Hom.:

AF XY:

0.0000519

AC XY:

AN XY:

134976

show subpopulations

Gnomad AFR exome

AF:

0.0000648

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000111

Gnomad SAS exome

AF:

0.0000654

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000799

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000876

AC:

128

AN:

1461606

Hom.:

Cov.:

AF XY:

0.0000839

AC XY:

AN XY:

727082

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000580

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000105

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.0000657

AC:

AN:

152252

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74440

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.000415

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000882

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000162

Hom.:

Bravo

AF:

0.0000718

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000519

AC:

ExAC

AF:

0.0000826

AC:

Asia WGS

AF:

0.000866

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hypertrophic cardiomyopathy

Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 05, 2019	The p.Arg733Cys variant in MYBPC3 has been reported in at least 2 individuals with HCM (Van Driest 2004, LMM data). This variant has been identified in 9/126440 of European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org/; dbSNP rs397515956). This variant has been reported in ClinVar (Variant ID: 42607). Clinvar: VUS (5 submitters). Arginine (Arg) at position 733 is not conserved in mammals, or evolutionarily distant species and the change to cystine (Cys) was predicted to be benign using a computational tool clinically validated by our laboratory. This tool's benign prediction is estimated to be correct 89% of the time (Jordan 2011). In addition, this amino acid change is present in the rhesus macaque. In summary, the clinical significance of the p.Arg733Cys variant is uncertain. -
Uncertain significance, criteria provided, single submitter	research	Agnes Ginges Centre for Molecular Cardiology, Centenary Institute	Mar 22, 2017	This MYBPC3 Arg733Cys variant has been reported in 1 HCM proband by Van Driest et al. (2004) in their cohort of 389 unrelated HCM probands, where only the MYBPC3 gene was screened and 2 HCM probands by Walsh et al. (2017). The variant has also been identified in 1 control (Kapplinger JD, et al., 2014) and is present in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/) at an allele frequency >0.00008, which is higher then expected for HCM. We have identified this variant in 1 HCM proband who experienced a resuscitated cardiac arrest. This proband also carries an additional known pathogenic splice variant in MYBPC3 (c.1928-2A>G). Computational analyses (SIFT, MutationTaster) support a potentially deleterious effect. However, a tool specifically designed to predict the effects of missense variants in HCM genes (Jordan DM, et al., 2011), predicts this variant to have a "benign" affect. Based on the elevated allele frequency in the general population, observation of the variant in 1 control and a total of 4 HCM probands, we classify MYBPC3 Arg733Cys as variant of "uncertain significance". -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Sep 19, 2022	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 733 of the MYBPC3 protein (p.Arg733Cys). This variant is present in population databases (rs397515956, gnomAD 0.02%). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 15519027, 27532257). ClinVar contains an entry for this variant (Variation ID: 42607). An algorithm developed specifically for the MYBPC3 gene suggests that this missense change is likely to be tolerated (PMID: 21310275). 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Dec 01, 2023	This missense variant replaces arginine with cysteine at codon 733 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). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in a few individuals affected with hypertrophic cardiomyopathy (PMID: 15519027, 27532257, 33782553) and in a healthy control individual (PMID: 24510615). This variant has been identified in 17/280042 chromosomes 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. -

Hypertrophic cardiomyopathy 4

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Uncertain significance, criteria provided, single submitter	curation	SIB Swiss Institute of Bioinformatics	May 31, 2018	This variant is interpreted as a Uncertain Significance - Insufficient Evidence, for Cardiomyopathy, familial hypertrophic, 4, in Autosomal Dominant manner. The following ACMG Tag(s) were applied: PM2-Supporting =>PM2 downgraded in strength to Supporting. -

not specified

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Stanford Center for Inherited Cardiovascular Disease, Stanford University

Feb 25, 2015

Note 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.Arg733Cys Given weak case data and the fact that few pathogenic variants in MYBPC3 are missense, we consider it a variant of uncertain significance. The variant has been seen in at least one case of HCM (not including this patient's family). There is no segregation data available. Dr. Ackerman's group reported the variant in one patient with HCM from their 389 patient Mayo cohort (van Driest et al 2004). No ancestry or segregation data was reported. They only analyzed MYBPC3 in that study. The arginine at codon 733 is only partially conserved across species, with a histidine at that position in some non-mammals. This is a non-conservative amino acid substitution (Grantham score 180). I could find only one nearby missense variant (p.Arg726Cys (HGMD, Seidmans' database)). Of note, the majority of disease-causing variants in MYBPC3 are splice, nonsense, or frameshift variants. The splicing algorithms that mutationtaster uses did not predict a significant effect on splicing. -

Hypertrophic cardiomyopathy 4;C3715165:Left ventricular noncompaction 10

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 01, 2021

- -

Cardiomyopathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Apr 25, 2023

This missense variant replaces arginine with cysteine at codon 733 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with hypertrophic cardiomyopathy (PMID: 15519027, 27532257, 33782553). This variant has been identified in 17/280042 chromosomes 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. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Nov 07, 2023

Reported in individuals referred for HCM genetic testing at GeneDx and in the published literature (PMID: 15519027, 27532257) as well as in one control individual (PMID: 24510615); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 21415409, 27532257, 24510615, 34426522, 21310275, 30681346, 30937429, 26659599, 31983221, 15519027) -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 26, 2023

The p.R733C variant (also known as c.2197C>T), located in coding exon 23 of the MYBPC3 gene, results from a C to T substitution at nucleotide position 2197. The arginine at codon 733 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been reported in association with hypertrophic cardiomyopathy (HCM), although clinical details were limited (Van Driest SL et al. J. Am. Coll. Cardiol., 2004 Nov;44:1903-10; Walsh R et al. Genet. Med., 2017 Feb;19:192-203). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.24

CardioboostCm

Benign

0.0094

BayesDel_addAF

Uncertain

0.082

BayesDel_noAF

Uncertain

0.11

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.28

T;T;T

Eigen

Benign

-0.022

Eigen_PC

Benign

0.18

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.85

T;T;T

M_CAP

Uncertain

0.11

MetaRNN

Benign

0.18

T;T;T

MetaSVM

Benign

-0.85

MutationAssessor

Benign

1.3

L;.;.

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Benign

0.40

PROVEAN

Benign

-2.1

N;.;N

REVEL

Uncertain

0.33

Sift

Benign

0.19

T;.;T

Sift4G

Benign

0.18

T;T;T

Vest4

0.79

MVP

0.84

MPC

0.94

ClinPred

0.20

GERP RS

5.4

Varity_R

0.17

gMVP

0.67

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