11-47336000-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 2P and 16B. PM1BP4_StrongBP6_Very_StrongBS2

The NM_000256.3(MYBPC3):c.2614G>A(p.Glu872Lys) variant causes a missense change. The variant allele was found at a frequency of 0.0000927 in 1,521,574 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00014 ( 0 hom., cov: 30)

Exomes 𝑓: 0.000087 ( 3 hom. )

Consequence

MYBPC3
NM_000256.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13

Conservation

PhyloP100: 5.83

Publications

2 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: Benign. The variant received -14 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 28 uncertain in NM_000256.3

BP4

Computational evidence support a benign effect (MetaRNN=0.020652771).

BP6

Variant 11-47336000-C-T is Benign according to our data. Variant chr11-47336000-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 42647.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Homozygotes in GnomAdExome4 at 3 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYBPC3	NM_000256.3 link	c.2614G>A	p.Glu872Lys	missense_variant	Exon 26 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.2614G>A	p.Glu872Lys	missense_variant	Exon 26 of 35	5	NM_000256.3	ENSP00000442795.1	Q14896-1
MYBPC3	ENST00000399249.6 link	c.2614G>A	p.Glu872Lys	missense_variant	Exon 25 of 34	5		ENSP00000382193.2	A8MXZ9
MYBPC3	ENST00000544791.1 link	n.*119G>A		non_coding_transcript_exon_variant	Exon 26 of 27	5		ENSP00000444259.1	F5GZR4
MYBPC3	ENST00000544791.1 link	n.*119G>A		3_prime_UTR_variant	Exon 26 of 27	5		ENSP00000444259.1	F5GZR4

Frequencies

GnomAD3 genomes

AF:

0.000132

AC:

AN:

151940

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000967

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000982

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

GnomAD2 exomes

AF:

0.000535

AC:

AN:

173718

AF XY:

0.000416

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00373

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000149

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000748

GnomAD4 exome

AF:

0.0000869

AC:

119

AN:

1369516

Hom.:

Cov.:

AF XY:

0.0000773

AC XY:

AN XY:

672896

show subpopulations

African (AFR)

AF:

0.0000331

AC:

AN:

30216

American (AMR)

AF:

0.00304

AC:

105

AN:

34548

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

21820

East Asian (EAS)

AF:

0.0000277

AC:

AN:

36080

South Asian (SAS)

AF:

0.0000560

AC:

AN:

71458

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50472

Middle Eastern (MID)

AF:

0.000260

AC:

AN:

3846

European-Non Finnish (NFE)

AF:

0.00000282

AC:

AN:

1064754

Other (OTH)

AF:

0.0000710

AC:

AN:

56322

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000145

AC:

AN:

152058

Hom.:

Cov.:

AF XY:

0.0000942

AC XY:

AN XY:

74308

show subpopulations

African (AFR)

AF:

0.000121

AC:

AN:

41474

American (AMR)

AF:

0.00105

AC:

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5166

South Asian (SAS)

AF:

0.00

AC:

AN:

4812

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10548

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

67982

Other (OTH)

AF:

0.00

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00130

Hom.:

Bravo

AF:

0.000344

ExAC

AF:

0.000365

AC:

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Nov 12, 2024

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

See Variant Classification Assertion Criteria. -

Aug 22, 2016

Stanford Center for Inherited Cardiovascular Disease, Stanford University

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:provider interpretation

p.Glu872Lys (E872K; c.2614 G>A) in the MYBPC3 gene. We classify it as a variant of unknown significance. This variant has not previously been reported in individuals with HCM. There is no published segregation data. At SCICD, it has segregated with disease in a brother and sister with HCM. Variation at the following adjacent residue has been reported in the HGMD to be associated with cardiomyopathy: Pro873His, Pro873Leu. This supports the functional importance of this region of the protein. This is a non-conservative amino acid change, resulting in the replacement of a glutamic acid (acidic) with a lysine (basic). Glutamic acid at this location is 100% conserved across 9 mammalian species. The adjacent residues are also highly conserved. In silico analysis with PolyPhen-2 (http://genetics.bwh.harvard.edu/pph2/) predicts the variant to be "Probably Damaging" with a score of 0.993. SIFT predicts it to be deleterious, with a score of 0.01. ExAC data (aug 2016): All: AF: 0.00058673 38/64766 alleles Highest frequency - Latinos: AF: 0.00663796 37/5574 It has been seen in 1 out of ~7240 individuals from publicly available population datasets as of January 24, 2014. More specifically, it was seen in 1 out of 64 individuals of Mexican ancestry in 1000 Genomes, for a MAF in that population of 0.0078 (1/128 alleles). This may argue against pathogenicity, since this is the same ethnicity as our patient. In 1000 Genomes, the overall Minor Allele Frequency (MAF) was 0.0005 (1/2178 alleles). This variant is not listed in the NHLBI Exome Sequencing Project dataset (http://evs.gs.washington.edu/EVS/), which currently includes variant calls on ~4150 Caucasian and ~2000 African American individuals. -

Sep 20, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:2

Jul 18, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

p.Glu872Lys in exon 26 of MYBPC3: This variant is not expected to have clinical significance because it is not located within the splice consensus sequence. It has been identified in 0.7% (37/5574) of Latino chromosomes, including 2 homozy gotes, by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org ; dbSNP rs190765116). -

Jan 17, 2022

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

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: MYBPC3 c.2614G>A (p.Glu872Lys) results in a conservative amino acid change located in the Fibronectin type III domain (IPR003961) 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 0.00054 in 173718 control chromosomes, predominantly at a frequency of 0.0037 within the Latino subpopulation in the gnomAD database, including 4 homozygotes. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 4 fold of the estimated maximal expected allele frequency for a pathogenic variant in MYBPC3 causing Cardiomyopathy phenotype (0.001), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Latino origin. c.2614G>A has been reported in the literature in individuals affected with Cardiomyopathy, without strong evidence for causality (Bursetein_2021, Murphy_2016). Co-occurrences with other pathogenic variants have been reported (MYBPC3 c.3811C>T, p.R1271* - internal testing; LMOD2 c.1193G>A, p.W398* Bursetein_2021), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Ten clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as benign(n=2) and likely benign (n=8). Based on the evidence outlined above, the variant was classified as benign. -

Hypertrophic cardiomyopathy

Benign:2

Sep 23, 2024

All of Us Research Program, National Institutes of Health

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 14, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hypertrophic cardiomyopathy;C0023976:Long QT syndrome

Benign:1

Jun 05, 2018

Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Left ventricular noncompaction 10

Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Cardiomyopathy

Benign:1

Nov 14, 2018

Color Diagnostics, LLC DBA Color Health

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hypertrophic cardiomyopathy 4

Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Cardiovascular phenotype

Benign:1

Nov 27, 2018

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Jun 14, 2019

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely 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

0.25

CardioboostCm

Benign

0.081

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Uncertain

0.010

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.36

T;T;T

Eigen

Pathogenic

0.73

Eigen_PC

Pathogenic

0.71

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.92

D;D;D

M_CAP

Uncertain

0.21

MetaRNN

Benign

0.021

T;T;T

MetaSVM

Benign

-0.43

MutationAssessor

Benign

1.9

L;.;.

PhyloP100

5.8

PrimateAI

Uncertain

0.72

PROVEAN

Uncertain

-2.9

D;.;D

REVEL

Benign

0.29

Sift

Benign

0.039

D;.;D

Sift4G

Uncertain

0.021

D;D;D

Vest4

0.75

MVP

0.90

MPC

0.88

ClinPred

0.16

GERP RS

5.3

Varity_R

0.51

gMVP

0.71

Mutation Taster

=72/28

polymorphism

(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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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