rs727504418

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 1P and 0B. PP3

The NM_000256.3(MYBPC3):c.2671C>T(p.Arg891Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000185 in 1,564,140 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R891Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 30)

Exomes 𝑓: 0.000020 ( 0 hom. )

Consequence

MYBPC3
NM_000256.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:9

Conservation

PhyloP100: 1.62

Publications

4 publications found

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 Gene-Disease associations (from GenCC):

hypertrophic cardiomyopathy
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
hypertrophic cardiomyopathy 4
Inheritance: AD, AR Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
left ventricular noncompaction 10
Inheritance: AR, AD Classification: DEFINITIVE, MODERATE, LIMITED Submitted by: Ambry Genetics
familial isolated dilated cardiomyopathy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
arrhythmogenic right ventricular cardiomyopathy
Inheritance: AD Classification: LIMITED Submitted by: ClinGen
atrial fibrillation
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
dilated cardiomyopathy
Inheritance: AD Classification: LIMITED Submitted by: ClinGen

MYBPC3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.824

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYBPC3	NM_000256.3 link	c.2671C>T	p.Arg891Trp	missense_variant	Exon 26 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.2671C>T	p.Arg891Trp	missense_variant	Exon 26 of 35	5	NM_000256.3	ENSP00000442795.1	Q14896-1
MYBPC3	ENST00000399249.6 link	c.2671C>T	p.Arg891Trp	missense_variant	Exon 25 of 34	5		ENSP00000382193.2	A8MXZ9
MYBPC3	ENST00000544791.1 link	n.*176C>T		non_coding_transcript_exon_variant	Exon 26 of 27	5		ENSP00000444259.1	F5GZR4
MYBPC3	ENST00000544791.1 link	n.*176C>T		3_prime_UTR_variant	Exon 26 of 27	5		ENSP00000444259.1	F5GZR4

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152182

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:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000263

AC:

AN:

189998

AF XY:

0.0000193

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000148

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000235

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000198

AC:

AN:

1411958

Hom.:

Cov.:

AF XY:

0.0000186

AC XY:

AN XY:

698430

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31686

American (AMR)

AF:

0.00

AC:

AN:

37934

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24662

East Asian (EAS)

AF:

0.000406

AC:

AN:

36924

South Asian (SAS)

AF:

0.0000378

AC:

AN:

79270

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51098

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4506

European-Non Finnish (NFE)

AF:

0.00000919

AC:

AN:

1087606

Other (OTH)

AF:

0.00

AC:

AN:

58272

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.455

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152182

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74338

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41444

American (AMR)

AF:

0.00

AC:

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.000193

AC:

AN:

5190

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68028

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000172

Hom.:

ExAC

AF:

0.0000166

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:3

Feb 06, 2024

GeneDx

Significance:Uncertain significance

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; This variant is associated with the following publications: (PMID: 27532257, 32183154, 31447099, Murakami2014, Maeda2009, 32600061, 25611685) -

Jun 27, 2023

Revvity Omics, Revvity

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 01, 2020

CeGaT Center for Human Genetics Tuebingen

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hypertrophic cardiomyopathy

Uncertain:2

Feb 05, 2024

All of Us Research Program, National Institutes of Health

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This missense variant replaces arginine with tryptophan at codon 891 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: 25611685, 27532257, 33495597), in individuals affected with dilated cardiomyopathy (PMID: 27532257, DOI:10.1016/j.fsigss.2009.08.094), and in an individual affected with left ventricular noncompaction cardiomyopathy (PMID: 32183154). This variant has been identified in 6/221382 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. -

Aug 09, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

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 891 of the MYBPC3 protein (p.Arg891Trp). 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 individual(s) with MYBPC3-related conditions (PMID: 25611685, 27532257, 32183154, 32600061). ClinVar contains an entry for this variant (Variation ID: 177949). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest 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. -

not specified

Uncertain:1

May 15, 2019

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant classified as Uncertain Significance - Favor Pathogenic. The p.Arg891Trp variant in MYBPC3 has been reported in 1 individual with DCM (Maeda 2009) and as a de novo occurrence in 1 infant with HCM (Alfares 2015, LMM data). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID: 177949) and has been identified in 3/14552 East Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org). Computational prediction tools and conservation analysis suggest that the p.Arg891Trp variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, while there is some suspicion for a pathogenic role, the clinical significance of the p.Arg891Trp variant is uncertain. ACMG/AMP Criteria applied: PM2_Supporting, PM6, PP3. -

Hypertrophic cardiomyopathy 4;C3715165:Left ventricular noncompaction 10

Uncertain:1

Apr 01, 2022

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cardiomyopathy

Uncertain:1

Mar 16, 2023

Color Diagnostics, LLC DBA Color Health

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Cardiovascular phenotype

Uncertain:1

Apr 15, 2022

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.R891W variant (also known as c.2671C>T), located in coding exon 26 of the MYBPC3 gene, results from a C to T substitution at nucleotide position 2671. The arginine at codon 891 is replaced by tryptophan, an amino acid with dissimilar properties. This variant has been detected in individuals from cohorts with or referred for genetic testing for dilated cardiomyopathy, hypertrophic cardiomyopathy, and non-compaction cardiomyopathy, and a cohort not selected for the presence of known cardiomyopathy; however details were limited (Maeda K et al. Forensic Sci Int Genetics Suppl Series 2, 2009 499-500, doi:10.1016/j.fsigss.2009.08.094; Alfares AA et al. Genet Med, 2015 Nov;17:880-8; Walsh R et al. Genet Med, 2017 02;19:192-203; Zouk et al. Am J Hum Genet, 2019 09;105:588-605; Hirono K et al. Circ Genom Precis Med, 2020 08;13:e002940; Harper AR et al. Nat Genet, 2021 02;53:135-142). This amino acid position is highly 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

0.31

CardioboostCm

Pathogenic

0.93

BayesDel_addAF

Uncertain

0.14

BayesDel_noAF

Uncertain

-0.040

CADD

Uncertain

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.43

T;T;T

Eigen

Uncertain

0.47

Eigen_PC

Uncertain

0.31

FATHMM_MKL

Uncertain

0.80

LIST_S2

Pathogenic

0.99

D;D;D

M_CAP

Uncertain

0.21

MetaRNN

Pathogenic

0.82

D;D;D

MetaSVM

Uncertain

0.052

MutationAssessor

Pathogenic

3.4

M;.;.

PhyloP100

1.6

PrimateAI

Uncertain

0.74

PROVEAN

Pathogenic

-6.5

D;.;D

REVEL

Uncertain

0.51

Sift

Uncertain

0.0010

D;.;D

Sift4G

Pathogenic

0.0010

D;D;D

Vest4

0.96

MVP

0.87

MPC

0.84

ClinPred

0.94

GERP RS

-0.88

Varity_R

0.62

gMVP

0.74

Mutation Taster

=4/96

disease causing

(source)

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

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rs727504418

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over