rs202147520

Positions:

chr11-47332144-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM1PP3

The NM_000256.3(MYBPC3):c.3742G>A(p.Gly1248Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000781 in 1,613,616 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 (★★).

Frequency

Genomes: 𝑓 0.000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000079 ( 0 hom. )

Consequence

MYBPC3
NM_000256.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:13

Conservation

PhyloP100: 4.76

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 3 ACMG points.

PM1

In a domain Ig-like C2-type 7 (size 93) in uniprot entity MYPC3_HUMAN there are 32 pathogenic changes around while only 0 benign (100%) in NM_000256.3

PP3

MetaRNN computational evidence supports a deleterious effect, 0.759

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYBPC3	NM_000256.3 linkuse as main transcript	c.3742G>A	p.Gly1248Arg	missense_variant	33/35	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.3742G>A	p.Gly1248Arg	missense_variant	33/35	5	NM_000256.3	ENSP00000442795	P4	Q14896-1
MYBPC3	ENST00000399249.6 linkuse as main transcript	c.3742G>A	p.Gly1248Arg	missense_variant	32/34	5		ENSP00000382193	A2

Frequencies

GnomAD3 genomes

AF:

0.0000657

AC:

AN:

152238

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

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:

0.000103

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000321

AC:

AN:

249120

Hom.:

AF XY:

0.0000370

AC XY:

AN XY:

135168

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000556

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000531

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000794

AC:

116

AN:

1461378

Hom.:

Cov.:

AF XY:

0.0000770

AC XY:

AN XY:

726980

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000980

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000657

AC:

AN:

152238

Hom.:

Cov.:

AF XY:

0.0000672

AC XY:

AN XY:

74374

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000103

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000112

Hom.:

Bravo

AF:

0.0000869

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000362

AC:

ExAC

AF:

0.0000331

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:5

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Apr 12, 2024	Identified in patients with HCM, DCM, alcoholic cardiomyopathy, and sudden death; in one family with DCM, the variant did not segregate with disease in two affected family members (PMID: 29773157, 18403758, 17908752, 22765922, 27532257, 28356264, 26899768, 28750076, 30847666, 27650965, 28074886, 30696458, 33782553, 32009526); 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: 21415409, 27532257, 23299917, 25637381, 17908752, 22765922, 27650965, 28356264, 28750076, 28679633, 30847666, 32841044, 33190526, 30696458, 18403758, 29773157, 33782553, 26899768, 28074886, 32009526) -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	Jan 03, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 05, 2019	The p.Gly1248Arg variant in MYBPC3 has been reported in at least 2 individuals with DCM (Cuenca 2016, Forleo 2017), 2 individuals with unexplained sudden death (Christiansen 2016, Neubauer 2017), and 2 individuals with HCM, including 1 child who carried a splice variant in MYBPC3 (Hofman 2007, Morita 2008, Coto 2012, Gómez 2017). However, the variant failed to segregate with DCM in 2 affected members of 1 family (Cuenca 2016). This variant has also been identified in 0.005% (6/111626) of European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs202147520). Computational prediction tools suggest that the p.Gly1248Arg variant may impact the protein, though conservation analysis show 2 mammals (orangutan and elephant) carry an arginine (Arg) at position 1248, suggesting that this change may be tolerated. Splice prediction tools predict that this variant may create a novel 3' splice site, though in vitro functional studies do not support a splicing impact (Ito 2017). In summary, the clinical significance of the p.Gly1248Arg variant is uncertain. The ACMG/AMP Criteria applied: BS4. -

Hypertrophic cardiomyopathy

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 06, 2023	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 1248 of the MYBPC3 protein (p.Gly1248Arg). This variant is present in population databases (rs202147520, gnomAD 0.006%). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 18403758, 22765922). ClinVar contains an entry for this variant (Variation ID: 42739). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Not Available". The arginine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Studies have shown that this missense change does not affect mRNA splicing (PMID: 28679633). 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	Feb 05, 2024	This missense variant replaces glycine with arginine at codon 1248 of the MYBPC3 protein. Computational prediction tools indicate that this variant has a neutral impact on protein structure and function. A functional mini-gene assay has shown that this variant may not cause aberrant splicing (PMID: 28679633). This variant has been reported in over ten unrelated individuals affected with hypertrophic cardiomyopathy (PMID: 18403758, 22765922, 27532257, 28356264, 30696458, 32841044, 33190526, 33495596, 33495597, ClinVar SCV000747929.1) including one individual who also carried a pathogenic variant in the MYBPC3 gene (PMID: 33190526). This variant has also been reported in three individuals affected with dilated cardiomyopathy (PMID: 26899768, 28750076, 30847666), in one individual affected with cardiomyopathy (PMID: 32009526), and in four young individuals affected with sudden cardiac death (PMID: 17908752, 27650965, 28074886, 37589201) including one carrying a pathogenic MYBPC3 splice variant (PMID: 17908752). This variant has been identified in 8/249120 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Although there is a suspicion that this variant may be associated with disease, additional studies are necessary 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

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	Jul 25, 2016	- -
Uncertain significance, no assertion criteria provided	research	CSER _CC_NCGL, University of Washington	Jun 01, 2014	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

May 03, 2021

Variant summary: MYBPC3 c.3742G>A (p.Gly1248Arg) results in a non-conservative amino acid change located in the Immunoglobulin subtype 2 domain (IPR003598) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.2e-05 in 249620 control chromosomes (gnomAD and publication data). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.3742G>A has been reported in the literature in individuals affected with hypertrophic cardiomyopathy or dilated cardiomyopathy (Hofman_2007, Morita_2008, Coto_2012, Cuenca_2016, Walsh_2017, Gomez_2017, Forleo_2017, Ware_2018, van Lint_2019). These reports do not provide unequivocal conclusions about association of the variant with Cardiomyopathy. Additionally, one co-occurrence with another pathogenic variant has been reported (MYBPC3 c.2149-2delA; Hofman_2007), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Hypertrophic cardiomyopathy 4;C3715165:Left ventricular noncompaction 10

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 16, 2021

- -

Cardiomyopathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Jan 02, 2024

This missense variant replaces glycine with arginine at codon 1248 of the MYBPC3 protein. Computational prediction tools indicate that this variant has a neutral impact on protein structure and function. A functional mini-gene assay has shown that this variant may not cause aberrant splicing (PMID: 28679633). This variant has been reported in over ten unrelated individuals affected with hypertrophic cardiomyopathy (PMID: 18403758, 22765922, 27532257, 28356264, 30696458, 32841044, 33190526, 33495596, 33495597, ClinVar SCV000747929.1) including one individual who also carried a pathogenic variant in the MYBPC3 gene (PMID: 33190526). This variant has also been reported in three individuals affected with dilated cardiomyopathy (PMID: 26899768, 28750076, 30847666), in one individual affected with cardiomyopathy (PMID: 32009526), and in four young individuals affected with sudden cardiac death (PMID: 17908752, 27650965, 28074886, 37589201) including one carrying a pathogenic MYBPC3 splice variant (PMID: 17908752). This variant has been identified in 8/249120 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Although there is a suspicion that this variant may be associated with disease, additional studies are necessary to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 26, 2022

The c.3742G>A (p.G1248R) alteration is located in exon 33 (coding exon 33) of the MYBPC3 gene. This alteration results from a G to A substitution at nucleotide position 3742, causing the glycine (G) at amino acid position 1248 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.63

CardioboostCm

Benign

0.053

BayesDel_addAF

Uncertain

0.094

BayesDel_noAF

Uncertain

0.070

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.75

D;T;T

Eigen

Benign

-0.23

Eigen_PC

Benign

-0.24

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.79

T;T;T

M_CAP

Pathogenic

0.58

MetaRNN

Pathogenic

0.76

D;D;D

MetaSVM

Benign

-0.76

MutationAssessor

Benign

0.025

N;.;.

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.59

PROVEAN

Pathogenic

-5.3

D;D;D

REVEL

Uncertain

0.37

Sift

Benign

0.039

D;D;D

Sift4G

Uncertain

0.017

D;D;D

Vest4

0.83

MVP

0.90

MPC

0.65

ClinPred

0.42

GERP RS

3.6

Varity_R

0.27

gMVP

0.98

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.19

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