rs200352299

Positions:

chr11-47341180-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM1BP4_Strong

The NM_000256.3(MYBPC3):c.1855G>A(p.Glu619Lys) variant causes a missense change. The variant allele was found at a frequency of 0.000484 in 1,602,324 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00034 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00050 ( 0 hom. )

Consequence

MYBPC3
NM_000256.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:12

Conservation

PhyloP100: 3.96

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_benign. Variant got -2 ACMG points.

PM1

In a domain Ig-like C2-type 4 (size 89) in uniprot entity MYPC3_HUMAN there are 31 pathogenic changes around while only 3 benign (91%) in NM_000256.3

BP4

Computational evidence support a benign effect (MetaRNN=0.025160968).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYBPC3	NM_000256.3 linkuse as main transcript	c.1855G>A	p.Glu619Lys	missense_variant	19/35	ENST00000545968.6	NP_000247.2	Q14896-1A5YM48

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
MYBPC3	ENST00000545968.6 linkuse as main transcript	c.1855G>A	p.Glu619Lys	missense_variant	19/35	5	NM_000256.3	ENSP00000442795.1	Q14896-1
MYBPC3	ENST00000399249.6 linkuse as main transcript	c.1855G>A	p.Glu619Lys	missense_variant	18/34	5		ENSP00000382193.2	A8MXZ9
MYBPC3	ENST00000544791.1 linkuse as main transcript	n.1855G>A		non_coding_transcript_exon_variant	19/27	5		ENSP00000444259.1	F5GZR4

Frequencies

GnomAD3 genomes

AF:

0.000342

AC:

AN:

152166

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000523

Gnomad ASJ

AF:

0.00519

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000323

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000493

AC:

113

AN:

229214

Hom.:

AF XY:

0.000539

AC XY:

AN XY:

124194

show subpopulations

Gnomad AFR exome

AF:

0.0000734

Gnomad AMR exome

AF:

0.000339

Gnomad ASJ exome

AF:

0.00551

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000359

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000416

Gnomad OTH exome

AF:

0.000708

GnomAD4 exome

AF:

0.000499

AC:

723

AN:

1450040

Hom.:

Cov.:

AF XY:

0.000517

AC XY:

372

AN XY:

720114

show subpopulations

Gnomad4 AFR exome

AF:

0.000241

Gnomad4 AMR exome

AF:

0.000255

Gnomad4 ASJ exome

AF:

0.00483

Gnomad4 EAS exome

AF:

0.0000256

Gnomad4 SAS exome

AF:

0.0000119

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000475

Gnomad4 OTH exome

AF:

0.000684

GnomAD4 genome

AF:

0.000341

AC:

AN:

152284

Hom.:

Cov.:

AF XY:

0.000363

AC XY:

AN XY:

74472

show subpopulations

Gnomad4 AFR

AF:

0.0000722

Gnomad4 AMR

AF:

0.000523

Gnomad4 ASJ

AF:

0.00519

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000323

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000776

Hom.:

Bravo

AF:

0.000465

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000959

AC:

ExAC

AF:

0.000372

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5Benign:12

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hypertrophic cardiomyopathy 4

Uncertain:2Benign:1

Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Uncertain significance, no assertion criteria provided	clinical testing	Knight Diagnostic Laboratories, Oregon Health and Sciences University	Jan 27, 2016	- -

not specified

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 05, 2017	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 26, 2015	p.Glu619Lys in exon 19 of MYBPC3: This variant has been previously identified i n >10 individuals with varying cardiomyopathies including DCM, HCM, LVNC, and WP W (Moller 2009, Frisso 2009, Brito 2012, Kassem 2013, LMM unpublished data); how ever, at least three of these individuals carry an additional disease-causing va riant. Furthermore, this variant did not segregate with disease in 3 affected re latives (LMM unpublished data, pers. comm.). This variant has also been identifi ed in 0.1% (41/30772) European chromosomes by the Exome Aggregation Consortium ( ExAC, http://exac.broadinstitute.org/; dbSNP rs200352299). Lastly, glutamic acid (Glu) at position 619 is not conserved in mammals or evolutionarily distant spe cies and the change to lysine (Lys) was predicted to be benign using a computati onal tool clinically validated by our laboratory. This tool's benign prediction is estimated to be correct 89% of the time (Jordan 2011). In summary, the presen ce of this variant in different cardiomyopathies, non-segregation, and frequency in the general population support that this variant is likely benign. -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 26, 2020	Variant summary: MYBPC3 c.1855G>A (p.Glu619Lys) results in a conservative amino acid change located in the Immunoglobulin subtype domain (IPR003599) of the encoded protein sequence. Two of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00049 in 229814 control chromosomes, predominantly at a frequency of 0.00042 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 13 fold of the estimated maximal expected allele frequency for a pathogenic variant in MYBPC3 causing Dilated Cardiomyopathy phenotype (3.1e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.1855G>A has been reported in the literature in individuals affected with both Dilated and Hypertrophic Cardiomyopathy (Chung_2007, Moller_2009, Kassem_2013, Brito_2012, Marsiglia_2013, Sousa_2019). Co-occurrences with other pathogenic variants have been reported (MYBPC3, p.Ala558lysfsX9; MYBPC3 c.1505G>A , p.R502Q ; MYH7 c.1988G>A, p.R663H ; MYBPC3, p.L1221fs), providing supporting evidence for a benign role (Kassem_2013, Brito_2012, Marsiglia_2013). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eleven other ClinVar submitters (evaluation after 2014) cite the variant as likely benign/benign (n=9) or uncertain significance (n=2). Based on the evidence outlined above, the variant was classified as likely benign. -

Primary familial hypertrophic cardiomyopathy

Uncertain:2

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

Left ventricular noncompaction 10

Uncertain:1Benign:1

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -
Uncertain significance, no assertion criteria provided	clinical testing	Knight Diagnostic Laboratories, Oregon Health and Sciences University	Jan 27, 2016	- -

Cardiomyopathy

Benign:2

Benign, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	May 09, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Apr 20, 2018	- -

Hypertrophic cardiomyopathy

Benign:2

Likely benign, criteria provided, single submitter	research	Genetics and Genomics Program, Sidra Medicine	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

not provided

Benign:1

Likely benign, no assertion criteria provided

provider interpretation

Stanford Center for Inherited Cardiovascular Disease, Stanford University

Apr 19, 2017

p.Glu619Lys (c.1855 G>A) in MYBPC3 (NM_000256.3) We briefly re-reviewed this variant in April 2017, focusing on gnomAD and ClinVar. We did not re-assess case data. GeneDx initially classified the variant as a known disease-causing mutation, then a variant of uncertain significance, now likely benign. Given the frequency in reference samples (including 0.56% of Ashkenazi Jews), frequent co-occurrence with other pathogenic variants, and the fact that many cases are Ashkenazi Jewish, we consider this variant likely benign. ClinVar classifications (as of April 19, 2017): benign (Invitae), likely benign (GeneDx, LMM). The variant has been seen in multiple cases of HCM and DCM however many of them had another pathogenic variant. Frisso et al (2009) first reported the variant in one of 39 patients with pediatric onset HCM recruited from the South of Italy (more specific ancestry is not reported). They analyzed 8 sarcomere genes. Moller et al (2009) observed the variant in two brothers with dilated cardiomyopathy from their Danish cohort of 31 patients with dilated cardiomyopathy (more specific ancestry is not reported). Brito et al (2012) observed the variant in two unrelated patients with HCM from their Portuguese cohort of 77 HCM patients who underwent analysis of 5 sarcomere genes (again, specific individual ancestry was not provided). One patient was a compound heterozygote for this variant and p.Arg502Gln in MYBPC3, which we classify as very likely disease causing. While they note that these patients had a family history of HCM they unfortunately do not provide any segregation data. Kassem et al (2012) reported two of 192 Egyptian patients with cardiomyopathy who had sequencing of MYBPC3, MYH7, and TNNT2. One patient was a compound heterozygote for this variant and for p.Ala558lysfsX9, which we have not reviewed but would classify as either likely or very likely disease causing based on strong evidence that frameshift variants in MYBPC3 cause disease. Another patient carried only p.Glu619Lys and had left ventricular non-compaction without left ventricular hypertrophy. The Seidmans' online database notes a direct submission to them by Peng et al, with no phenotypic data provided (http://genepath.med.harvard.edu/~seidman/outdated-mutdb/muts/MYBPC3_Glu619Lys.html). Marsiglia et al (2013) observed the variant in one of 268 HCM patients from their Brazilian cohort who underwent analysis of MYH7, MYBPC3, and TNNT2. This patient was a compound heterozygote for this variant and a frameshift variant. The variant is not listed in ClinVar. Internal case data from the genetic testing labs suggests the variant may not be pathogenic and may be more prevalent in Ashkenazi Jews. Specifically, the Glu619Lys variant has been identified in multiple families tested for HCM or DCM at GeneDx, and approximately one third of these families identified themselves as having an Ashkenazi Jewish background. Additionally, approximately one third of the families found to harbor the Glu619Lys variant also carried a separate disease-causing mutation associated with cardiomyopathy, suggesting that Glu619Lys may not be a primary disease-causing mutation on its own. The Gly619Lys variant has also been detected in multiple individuals referred for HCM or DCM testing at the Laboratory for Molecular Medicine, Partners Healthcare Center for Personalized Genetic Medicine, and approximately half of these patients were reportedly of Ashkenazi Jewish background (personal communication to GeneDx from H. Rehm), again suggesting that Glu619Lys may be a common variant in the Ashkenazi Jewish population. One of the LMM families is described in Ball et al (2012). In a publication by LMM on their broad DCM panel, they describe a 19yo woman with DCM and a family history of DCM who carries this variant. Ancestry is noted as White. In silico analysis with PolyPhen-2 predicts the variant to be possibly damaging (HumVar score 0.426). The glutamic acid at codon 619 is not -

Cardiovascular phenotype

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 29, 2018

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. -

MYBPC3-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 07, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

CardioboostCm

Benign

0.029

BayesDel_addAF

Benign

-0.022

BayesDel_noAF

Uncertain

0.050

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.42

T;T;T

Eigen

Uncertain

0.23

Eigen_PC

Uncertain

0.27

FATHMM_MKL

Uncertain

0.89

LIST_S2

Pathogenic

0.99

D;D;D

M_CAP

Uncertain

0.22

MetaRNN

Benign

0.025

T;T;T

MetaSVM

Benign

-0.51

MutationAssessor

Benign

0.89

L;.;.

PrimateAI

Uncertain

0.58

PROVEAN

Uncertain

-2.5

D;.;D

REVEL

Uncertain

0.55

Sift

Uncertain

0.023

D;.;D

Sift4G

Uncertain

0.0050

D;D;D

Vest4

0.67

MVP

0.86

MPC

0.50

ClinPred

0.099

GERP RS

3.9

Varity_R

0.30

gMVP

0.72

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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