rs193922377

Positions:

chr11-47343051-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM1

The NM_000256.3(MYBPC3):c.1321G>A(p.Glu441Lys) variant causes a missense change. The variant allele was found at a frequency of 0.000122 in 1,613,118 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00016 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00012 ( 0 hom. )

Consequence

MYBPC3
NM_000256.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:21B:1

Conservation

PhyloP100: 5.76

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 2 ACMG points.

PM1

In a domain Ig-like C2-type 2 (size 90) in uniprot entity MYPC3_HUMAN there are 21 pathogenic changes around while only 3 benign (88%) in NM_000256.3

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYBPC3	NM_000256.3 linkuse as main transcript	c.1321G>A	p.Glu441Lys	missense_variant	15/35	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.1321G>A	p.Glu441Lys	missense_variant	15/35	5	NM_000256.3	ENSP00000442795	P4	Q14896-1
MYBPC3	ENST00000399249.6 linkuse as main transcript	c.1321G>A	p.Glu441Lys	missense_variant	14/34	5		ENSP00000382193	A2
MYBPC3	ENST00000544791.1 linkuse as main transcript	c.1321G>A	p.Glu441Lys	missense_variant, NMD_transcript_variant	15/27	5		ENSP00000444259

Frequencies

GnomAD3 genomes

AF:

0.000158

AC:

AN:

152240

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000193

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000162

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000138

AC:

AN:

246694

Hom.:

AF XY:

0.000179

AC XY:

AN XY:

133988

show subpopulations

Gnomad AFR exome

AF:

0.000462

Gnomad AMR exome

AF:

0.000175

Gnomad ASJ exome

AF:

0.000100

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000659

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000116

Gnomad OTH exome

AF:

0.000835

GnomAD4 exome

AF:

0.000118

AC:

173

AN:

1460760

Hom.:

Cov.:

AF XY:

0.000121

AC XY:

AN XY:

726586

show subpopulations

Gnomad4 AFR exome

AF:

0.000389

Gnomad4 AMR exome

AF:

0.000179

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000465

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000102

Gnomad4 OTH exome

AF:

0.000265

GnomAD4 genome

AF:

0.000158

AC:

AN:

152358

Hom.:

Cov.:

AF XY:

0.000161

AC XY:

AN XY:

74500

show subpopulations

Gnomad4 AFR

AF:

0.000192

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000162

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000214

Hom.:

Bravo

AF:

0.000204

ESP6500AA

AF:

0.000702

AC:

ESP6500EA

AF:

0.000236

AC:

ExAC

AF:

0.000149

AC:

EpiCase

AF:

0.000218

EpiControl

AF:

0.0000595

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:21Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:4Benign:1

Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2024	MYBPC3: BP4 -
Uncertain significance, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jan 09, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jul 25, 2024	Identified in patients with cardiomyopathy referred for genetic testing at GeneDx and in published literature (PMID: 18533079, 20173211, 20414521, 20624503, 22765922, 23233322, 26090888, 30871747, 30972196, 37652022, 24093860, 37431535); Observed in individuals with HCM who harbored co-occurring pathogenic cardiogenetic variants; one laboratory reports that an internal patient who also has a pathogenic MYBPC3 variant appeared to have an earlier onset of disease and a more severe presentation relative to the other patients that harbor p.(E441K) in isolation (PMID: 18533079, 20173211, 20624503, 32369506, 37431535; internal GeneDx data; ClinVar SCV000059030.5); Molecular modeling studies suggest that p.(E441K) causes conformational changes in cardiac myosin binding protein-C and interferes with normal binding/unbinding of the N-terminal complex, C1-motif-C2; however, the changes induced by p.(E441K) are less pronounced than those associated with the MYBPC3 p.(E258K) pathogenic variant (PMID: 25971843, 27267291); 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: 25971843, 20173211, 23233322, 23299917, 25637381, 22765922, 20624503, 26090888, 18533079, 27956910, 28518168, 21415409, 25524337, 27267291, 30645170, 30871747, 30731207, 30972196, 28420666, 24093860, 21835320, 20414521, 37652022, 37431535, 32369506, 30446606, 33049255) -

Hypertrophic cardiomyopathy 4

Uncertain:3

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	Mendelics	May 28, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jul 23, 2018	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. -

Hypertrophic cardiomyopathy

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 31, 2022	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 441 of the MYBPC3 protein (p.Glu441Lys). This variant is present in population databases (rs193922377, gnomAD 0.04%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with hypertrophic or dilated cardiomyopathy (PMID: 18533079, 20414521, 20624503, 21835320, 22765922, 23233322, 24093860, 26090888, 28420666, 30645170, 30731207, 30871747). ClinVar contains an entry for this variant (Variation ID: 36601). 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. Experimental studies have shown that this missense change affects MYBPC3 function (PMID: 30446606). 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	Jan 11, 2024	This missense variant replaces glutamic acid with lysine at codon 441 of the MYBPC3 protein. Computational prediction tools indicate that this variant has a neutral impact on protein structure and function. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in over 20 individuals affected with hypertrophic cardiomyopathy (PMID: 18533079, 20414521, 20624503, 21835320, 22765922, 23233322, 24093860, 26090888, 28420666, 30645170, 30972196, 32369506), and in individuals affected with dilated cardiomyopathy (PMID: 30871747, 35470680). However, some of these individuals also carried additional pathogenic variants that could explain the observed phenotype (PMID: 18533079, 20624503, 32369506, 37431535). In a study of two families, this variant has been observed in one affected individual but was absent in three other affected individuals (PMID: 30972196). A hypertrophic cardiomyopathy case-control study in Egypt (PMID: 37431535) has reported this variant in 24/514 cases (including 2 homozygotes), 8/400 controls; OR=2.4 (95% CI: 1.0 to 6.2); p-value=0.03. This variant occurs at an appreciable frequency in the general population and has been identified in 41/278096 chromosomes by the Genome Aggregation Database (gnomAD). In summary, this variant has been observed in affected individuals, as well as in the general population. 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. -
Uncertain significance, criteria provided, single submitter	research	Agnes Ginges Centre for Molecular Cardiology, Centenary Institute	Nov 26, 2018	The MYBPC3 Glu441Lys variant has been identified in multiple HCM probands, including several compound heterozygotes (Liu X, et al., 2015; Olivotto I, et al., 2008; Marsiglia JD, et al., 2010; Millat G, et al., 2010; Coto E, et al., 2012; Kassem HSh, et al., 2013, www.cardiodb.org/acgv/). We have identified this variant in 3 probands who were diagnosed at a young age (<18yo) and have severe hypertrophy, with maximum IVS measurements >30mm. All 3 probands also carry a second MYBPC3 variant, and one of these probands also carries a third variant in TNNT2. In one family MYBPC3 Glu441Lys did not segregate to another affected family member. The variant is present in the large Exome Aggregation Consortium dataset at an allele frequency of 0.00016 (http://exac.broadinstitute.org/), which is higher then expected for HCM. In silico tools SIFT, Polyphen2 and MutationTaster predict this variant to be deleterious. In summary, based on the adapted ACMG guidelines (Kelly MA, et al., 2018), the variant does not meet criteria for rarity (PM2) and as a result the identification of the variant in affected probands cannot be used, because only PP3 criteria are met, we classify MYBPC3 Glu441Lys as a variant of "uncertain significance" and suspect the variant may act as a modifier. -

Primary familial hypertrophic cardiomyopathy

Uncertain:3

Uncertain significance, no assertion criteria provided	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 02, 2015	- -
Uncertain significance, no assertion criteria provided	research	CSER _CC_NCGL, University of Washington	Jun 01, 2014	- -
Uncertain significance, no assertion criteria provided	clinical testing	Blueprint Genetics	Apr 11, 2014	- -

not specified

Uncertain:2

Uncertain significance, no assertion criteria provided	clinical testing	Stanford Center for Inherited Cardiovascular Disease, Stanford University	May 03, 2013	Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. MYBPC3 p.Glu441Lys We consider this a variant of uncertain significance. This variant has been seen in at least 7 presumably unrelated individuals with hypertrophic cardiomyopathy (HCM). I was unable to find any reports of this variant with dilated cardiomyopathy. Notably, all of the individuals with this variant had at least one other sarcomere variant. There is no segregation data available on this variant. Olivotto et al. (2008) reported p.Glu441Lys in one patient with HCM who also carried another MYBPC3 variant (p.Glu258Lys). No data regarding phase or severity of phenotype were reported. Millat et al. (2010) reported one individual with HCM who had three variants on one MYBPC3 allele (p.Glu441Lys, p.Gln76Ter, p.Gly279Ala) and also had an additional variant in MYH7 (p.Ile1927Phe). Unfortunately age of onset and severity were not reported. Marsiglia et al (2010) reported the variant in one individual with HCM in Brazil (article is in Portuguese, further details not available). p.Glu441Lys has also been observed in two other unrelated individuals with HCM tested at GeneDx. One individual had two MYBPC3 missense variants and one MYH7 missense variant, was diagnosed with HCM in childhood and required transplant. The other individual was diagnosed with HCM as a child and was a compound heterozygote for this variant and an MYBPC3 frameshift variant (both parents were unaffected). The Seidmans' research group report this variant online in an individual who presumably has HCM and is a compound heterozygote for this variant and p.Glu258Lys (Merk et al 2005, http://genepath.med.harvard.edu/~seidman/cg3/muts/MYBPC3_Glu441Lys.html) This is a semi conservative amino acid substitution of a polar negative Glutamic Acid with a polar positive Lysine. Glutamic Acid is highly conserved at position 441. This variant was not identified in 150 presumably healthy individuals by Olivotto et al (2008). Millat et al (2010) did not do population studies. NHLBI Exome Sequence Variant Database reports p.Glu441Lys in 2 out of 4243 European American individuals and 3 out of 2138 African American individuals. The phenotype of those individuals is not publicly available, however the cohorts that were merged to create this dataset were all either general population samples or samples recruited for common cardiovascular disease such as hypertension. Based on these data, we consider this variant to be of uncertain significance. This classification is based on the fact that it has primarily (possibly only) been seen in combination with other variants and it has not yet been demonstrated that this variant can cause cardiomyopathy on its own or that it contributes in a significant way when in combination with other variants. -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 09, 2015	The p.Glu441Lys variant in MYBPC3 has been observed in 10/62060 European chromos omes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs193922377) and has been reported in at least 9 individuals with HCM, 2 o f whom carried other pathogenic variants (Olivotto 2008, Marsiglia 2010, Millat 2010, Olivotto 2011, Coto 2012, Kassem 2013). Our laboratory has identified this variant in 2 individuals with HCM and 1 individual with biatrial enlargement wh o carried another pathogenic HCM variant. The individual carrying the additional pathogenic HCM variant appeared to have an earlier onset of disease and a more severe presentation relative to the other patients carrying the Glu441Lys varian t. Computational prediction tools and conservation analysis do not provide stro ng support for or against an impact to the protein. In summary, the clinical sig nificance of the p.Glu441Lys variant is uncertain. The available data raise the possibility that it is independently disease causing but milder in isolation but additional data is needed to confirm its significance. -

Cardiomyopathy

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	May 16, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Nov 21, 2022	This missense variant replaces glutamic acid with lysine at codon 441 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). To our knowledge, functional studies have not been performed for this variant. This variant has been reported in individuals affected with hypertrophic cardiomyopathy (PMID: 18533079, 20414521, 20624503, 21835320, 22765922, 23233322, 24093860, 26090888, 28420666, 30645170, 30972196, 32369506) or dilated cardiomyopathy (PMID: 30871747). However, some of these individuals also carried pathogenic variants in the same gene that could explain the observed phenotype (PMID: 18533079, 20624503, 32369506). In a study of two families, this variant has been observed in one affected individual but was absent in three other affected individuals (PMID: 30972196). This variant occurs at an appreciable frequency in the general population and has been identified in 41/278096 chromosomes by the Genome Aggregation Database (gnomAD). In summary, this variant has been observed in affected individuals, as well as in the general population. 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. -

Wolff-Parkinson-White pattern

Uncertain:1

Uncertain significance, no assertion criteria provided

research

Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine

Jul 14, 2017

This variant was identified in an individual with Wolff-Parkinson-White syndrome -

Left ventricular noncompaction 10

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jul 23, 2018

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). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Arrhythmogenic right ventricular dysplasia 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Sep 11, 2019

- -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 29, 2021

The c.1321G>A (p.E441K) alteration is located in exon 15 (coding exon 15) of the MYBPC3 gene. This alteration results from a G to A substitution at nucleotide position 1321, causing the glutamic acid (E) at amino acid position 441 to be replaced by a lysine (K). 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

Uncertain

0.44

CardioboostCm

Benign

0.042

BayesDel_addAF

Benign

-0.087

BayesDel_noAF

Uncertain

-0.030

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.69

D;T;T

Eigen

Uncertain

0.42

Eigen_PC

Uncertain

0.33

FATHMM_MKL

Uncertain

0.95

LIST_S2

Pathogenic

0.99

D;D;D

M_CAP

Uncertain

0.093

MetaRNN

Uncertain

0.58

D;D;D

MetaSVM

Benign

-0.73

MutationAssessor

Uncertain

2.2

M;.;.

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.52

PROVEAN

Uncertain

-3.7

D;.;D

REVEL

Uncertain

0.31

Sift

Uncertain

0.0020

D;.;D

Sift4G

Uncertain

0.0030

D;D;D

Vest4

0.72

MVP

0.84

MPC

0.72

ClinPred

0.12

GERP RS

3.8

Varity_R

0.48

gMVP

0.77

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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