rs727504249

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

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

The NM_000256.3(MYBPC3):c.103C>T(p.Arg35Trp) variant causes a missense change. The variant allele was found at a frequency of 0.0000149 in 1,609,360 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R35Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

MYBPC3
NM_000256.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:7

Conservation

PhyloP100: 3.65

Publications

8 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 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYBPC3	NM_000256.3 link	c.103C>T	p.Arg35Trp	missense_variant	Exon 2 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.103C>T	p.Arg35Trp	missense_variant	Exon 2 of 35	5	NM_000256.3	ENSP00000442795.1	Q14896-1
MYBPC3	ENST00000399249.6 link	c.103C>T	p.Arg35Trp	missense_variant	Exon 2 of 34	5		ENSP00000382193.2	A8MXZ9
MYBPC3	ENST00000544791.1 link	n.103C>T		non_coding_transcript_exon_variant	Exon 2 of 27	5		ENSP00000444259.1	F5GZR4

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152240

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000249

AC:

AN:

241004

AF XY:

0.0000456

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000366

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000137

AC:

AN:

1457120

Hom.:

Cov.:

AF XY:

0.0000193

AC XY:

AN XY:

724630

show subpopulations

African (AFR)

AF:

0.0000599

AC:

AN:

33408

American (AMR)

AF:

0.0000225

AC:

AN:

44432

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26020

East Asian (EAS)

AF:

0.00

AC:

AN:

39580

South Asian (SAS)

AF:

0.0000350

AC:

AN:

85702

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51584

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.0000108

AC:

AN:

1110402

Other (OTH)

AF:

0.0000332

AC:

AN:

60226

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.438

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152240

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74374

show subpopulations

African (AFR)

AF:

0.0000724

AC:

AN:

41464

American (AMR)

AF:

0.0000654

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5198

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

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:

68048

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.563

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000873

Hom.:

Bravo

AF:

0.0000378

ExAC

AF:

0.0000413

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Apr 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

MYBPC3: PS4:Moderate, PM2:Supporting, PS3:Supporting, BP4 -

Apr 04, 2019

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.Arg35Trp variant in MYBPC3 has been identified by our laboratory in 2 adults with HCM and 1 unaffected elderly adult. It has not been detected in large population studies. Computational analyses are conflicting as prediction tools suggest an impact to the protein while arginine (Arg) at position 35 is not conserved in evolution, raising the possibility that a change at this position may be tolerated. Additional information is needed to fully assess the clinical significance of the Arg35Trp variant. -

Hypertrophic cardiomyopathy

Uncertain:2

Aug 20, 2024

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 35 of the MYBPC3 protein (p.Arg35Trp). This variant is present in population databases (rs727504249, gnomAD 0.007%). This missense change has been observed in individual(s) with clinical features of hypertrophic cardiomyopathy (PMID: 20031602, 25558701, 27532257, 29030401, 35653365). ClinVar contains an entry for this variant (Variation ID: 177638). 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: 21297165). 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. -

Apr 16, 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 35 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. A functional study showed that the variant affects the interaction between the myosin binding protein C and the regulatory light chain of myosin (PMID: 21297165). This variant has been reported in 2 individuals affected with hypertrophic cardiomyopathy (PMID: 25558701, 29030401) and 1 individual who died suddenly from non-violent causes (PMID: 27930701). This variant has been identified in 6/241004 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. -

Cardiomyopathy

Uncertain:1

Feb 08, 2024

Color Diagnostics, LLC DBA Color Health

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This missense variant replaces arginine with tryptophan at codon 35 of the MYBPC3 protein. Computational prediction tools indicate that this variant has a deleterious impact on protein structure and function. A functional study showed that this variant may affect the interaction between the myosin binding protein C and the regulatory light chain of myosin (PMID: 21297165). This variant has been reported in three individuals affected with hypertrophic cardiomyopathy (PMID: 25558701, 27532257, 29030401, 32841044) and in one individual affected with sudden death (PMID: 27930701). This variant has been identified in 6/241004 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;C3715165:Left ventricular noncompaction 10

Uncertain:1

Sep 15, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cardiovascular phenotype

Uncertain:1

Jan 31, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.R35W variant (also known as c.103C>T), located in coding exon 2 of the MYBPC3 gene, results from a C to T substitution at nucleotide position 103. The arginine at codon 35 is replaced by tryptophan, an amino acid with dissimilar properties. This variant has been detected in hypertrophic cardiomyopathy (HCM) cohorts and a sudden death cohort; however, clinical details were limited (Ho CY et al. Circ Cardiovasc Genet, 2009 Aug;2:314-21; Sanchez O et al. PLoS ONE, 2016 Dec;11:e0167358; Walsh R et al. Genet. Med., 2017 02;19:192-203; Christensen KD et al. Genet. Med., 2018 12;20:1544-1553; Helms AS et al. Circ Genom Precis Med, 2020 Oct;13:396-405). A different variant affecting this codon (p.R35Q c.104G>A) has been detected in HCM cohorts; however details were limited (Walsh R et al. Genet. Med., 2017 02;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

Uncertain

0.36

CardioboostCm

Benign

0.094

BayesDel_addAF

Uncertain

0.055

BayesDel_noAF

Uncertain

0.020

CADD

Uncertain

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.46

T;T;T

Eigen

Uncertain

0.44

Eigen_PC

Uncertain

0.35

FATHMM_MKL

Uncertain

0.88

LIST_S2

Uncertain

0.93

D;D;D

M_CAP

Pathogenic

0.47

MetaRNN

Uncertain

0.70

D;D;D

MetaSVM

Uncertain

-0.17

MutationAssessor

Uncertain

2.9

M;.;.

PhyloP100

3.6

PrimateAI

Uncertain

0.59

PROVEAN

Uncertain

-2.6

D;D;D

REVEL

Uncertain

0.56

Sift

Uncertain

0.0010

D;D;D

Sift4G

Uncertain

0.0020

D;D;D

Polyphen

1.0

D;.;.

Vest4

0.81

MVP

0.89

MPC

0.83

ClinPred

0.76

GERP RS

3.3

Varity_R

0.61

gMVP

0.64

Mutation Taster

=19/81

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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rs727504249

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