rs727503167

Positions:

chr11-47332123-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PP3_Strong

The NM_000256.3(MYBPC3):c.3763G>A(p.Ala1255Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000328 in 1,613,512 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. A1255D) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000035 ( 0 hom. )

Consequence

MYBPC3
NM_000256.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:9B:1

Conservation

PhyloP100: 7.56

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 Likely_pathogenic. Variant got 6 ACMG points.

PM1

In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 15 uncertain in NM_000256.3

PP3

MetaRNN computational evidence supports a deleterious effect, 0.94

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYBPC3	NM_000256.3 linkuse as main transcript	c.3763G>A	p.Ala1255Thr	missense_variant	33/35	ENST00000545968.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYBPC3	ENST00000545968.6 linkuse as main transcript	c.3763G>A	p.Ala1255Thr	missense_variant	33/35	5	NM_000256.3	P4	Q14896-1
MYBPC3	ENST00000399249.6 linkuse as main transcript	c.3763G>A	p.Ala1255Thr	missense_variant	32/34	5		A2

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152252

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000683

AC:

AN:

248930

Hom.:

AF XY:

0.0000740

AC XY:

AN XY:

135088

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000261

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:

0.0000709

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000349

AC:

AN:

1461260

Hom.:

Cov.:

AF XY:

0.0000316

AC XY:

AN XY:

726918

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000268

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:

0.0000333

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152252

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74386

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000526

Hom.:

Bravo

AF:

0.0000189

ExAC

AF:

0.0000744

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:9Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 17, 2023	The MYBPC3 c.3763G>A; p.Ala1255Thr variant (rs727503167) is reported in the literature in numerous individuals affected with hypertrophic cardiomyopathy, including one individual with a pathogenic variant in trans in the same gene (Coppini 2014, Field 2022, Lopes 2013, Mademont-Soler 2017, Richard 2003). This variant has also been seen in one individual with dilated cardiomyopathy with a truncating variant in a different gene (Janin 2017). This variant is found in the general population with an overall allele frequency of 0.007% (19/280,328 alleles) in the Genome Aggregation Database (v2.1.1). An in vitro minigene assay demonstrates this variant does not affect splicing (Ito 2017). However computational analyses predict that this variant is deleterious (REVEL: 0.84). Due to conflicting information, the clinical significance of this variant is uncertain at this time. References: Coppini R et al. Clinical phenotype and outcome of hypertrophic cardiomyopathy associated with thin-filament gene mutations. J Am Coll Cardiol. 2014 Dec 23;64(24):2589-2600. PMID: 25524337. Field E et al. Cardiac myosin binding protein-C variants in paediatric-onset hypertrophic cardiomyopathy: natural history and clinical outcomes. J Med Genet. 2022 Aug;59(8):768-775. PMID: 34400558. Ito K et al. Identification of pathogenic gene mutations in LMNA and MYBPC3 that alter RNA splicing. Proc Natl Acad Sci U S A. 2017 Jul 18;114(29):7689-7694. PMID: 28679633. Janin A et al. Truncating mutations on myofibrillar myopathies causing genes as prevalent molecular explanations on patients with dilated cardiomyopathy. Clin Genet. 2017 Dec;92(6):616-623. PMID: 28436997. Lopes LR et al. Genetic complexity in hypertrophic cardiomyopathy revealed by high-throughput sequencing. J Med Genet. 2013 Apr;50(4):228-39. PMID: 23396983. Mademont-Soler I et al. Additional value of screening for minor genes and copy number variants in hypertrophic cardiomyopathy. PLoS One. 2017 Aug 3;12(8):e0181465. PMID: 28771489. Richard P et al. Hypertrophic cardiomyopathy: distribution of disease genes, spectrum of mutations, and implications for a molecular diagnosis strategy. Circulation. 2003 May 6;107(17):2227-32. PMID: 12707239. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Mar 20, 2024	Identified in a 31-year-old female with familial dilated cardiomyopathy (DCM); however, this individual also harbored a truncating FLNC variant (PMID: 28436997); 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: 25524337, 28840316, 24793961, 27532257, 12707239, 23396983, 28436997, 15115610, 28679633, 28771489, 25351510, 20031618, 28518168, Komissarova2021[article], Komissarova2022[article], 34400558, 37652022, 33782553) -

Cardiomyopathy

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	May 12, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Feb 06, 2023	This missense variant replaces alanine with threonine at codon 1255 of the MYBPC3 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). A minigene assay suggests that this variant does not affect normal RNA splicing (PMID: 28679633), however the clinical relevance of this observation is unknown. This variant has been reported in individuals affected with hypertrophic cardiomyopathy (PMID: 12707239, 20031618, 23396983, 25524337, 25351510, 27532257, 28771489, 33782553). It has also been reported in an individual affected with dilated cardiomyopathy (PMID: 28436997) and in an individual affected with sudden cardiac arrest (doi:10.1101/2022.10.27.22281332). This variant has been identified in 19/280328 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

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 24, 2024	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1255 of the MYBPC3 protein (p.Ala1255Thr). This variant is present in population databases (rs727503167, gnomAD 0.03%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 12707239, 20031618, 23396983, 25351510, 25524337, 27532257, 33782553, 34400558). ClinVar contains an entry for this variant (Variation ID: 164023). 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. 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 13, 2023	This missense variant replaces alanine with threonine at codon 1255 of the MYBPC3 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). A minigene assay suggests that this variant does not affect normal RNA splicing (PMID: 28679633), however the clinical relevance of this observation is unknown. This variant has been reported in individuals affected with hypertrophic cardiomyopathy (PMID: 12707239, 20031618, 23396983, 25524337, 25351510, 27532257, 28771489, 33782553). It has also been reported in an individual affected with dilated cardiomyopathy (PMID: 28436997) and in an individual affected with sudden cardiac arrest (doi:10.1101/2022.10.27.22281332). This variant has been identified in 19/280328 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. -

Primary familial hypertrophic cardiomyopathy

Pathogenic:1

Likely pathogenic, flagged submission

clinical testing

Blueprint Genetics

Nov 02, 2015

- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Aug 02, 2019

The p.Ala1255Thr variant in MYBPC3 has been identified in 7 individuals with hypertrophic cardiomyopathy, including one individual who also carried a heterozygous, likely pathogenic variant in another gene (Richard 2003, Lopes 2013, Coppini 2014, Walsh 2017, LMM data). It was also reported in 1 individual with DCM who also carried a frameshift variant in FLNC (Janin 2017). It has been identified in 0.028% (10/35350) of Latino chromosomes by gnomAD (http://gnomad.broadinstitute.org) and reported in ClinVar (Variation ID# 164023). Computational prediction tools and conservation analysis suggest that the p.Ala1255Thr variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: BS1_Supporting, PP3. -

Hypertrophic cardiomyopathy 4

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

Cardiovascular phenotype

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 11, 2021

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.78

CardioboostCm

Uncertain

0.23

BayesDel_addAF

Pathogenic

0.25

BayesDel_noAF

Pathogenic

0.42

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.84

D;T;T

Eigen

Pathogenic

0.92

Eigen_PC

Pathogenic

0.82

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.94

D;D;D

M_CAP

Pathogenic

0.59

MetaRNN

Pathogenic

0.94

D;D;D

MetaSVM

Pathogenic

0.84

MutationAssessor

Pathogenic

3.7

H;.;.

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.58

PROVEAN

Uncertain

-3.6

D;.;D

REVEL

Pathogenic

0.84

Sift

Pathogenic

0.0

D;.;D

Sift4G

Pathogenic

0.0

D;D;D

Vest4

0.98

MVP

0.93

MPC

0.81

ClinPred

0.98

GERP RS

5.5

Varity_R

0.91

gMVP

0.98

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.080

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