11-47332658-C-T

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_ModerateBP6

The NM_000256.3(MYBPC3):c.3535G>A(p.Glu1179Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000276 in 1,613,518 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 0.00038 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00026 ( 0 hom. )

Consequence

MYBPC3
NM_000256.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:12O:1

Conservation

PhyloP100: 3.08

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 -3 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.107124954).

BP6

Variant 11-47332658-C-T is Benign according to our data. Variant chr11-47332658-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 42719.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=9, Benign=2, Uncertain_significance=4, not_provided=1}. Variant chr11-47332658-C-T is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYBPC3	NM_000256.3 link	c.3535G>A	p.Glu1179Lys	missense_variant	Exon 32 of 35	ENST00000545968.6	NP_000247.2	Q14896-1A5YM48

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYBPC3	ENST00000545968.6 link	c.3535G>A	p.Glu1179Lys	missense_variant	Exon 32 of 35	5	NM_000256.3	ENSP00000442795.1		Q14896-1
MYBPC3	ENST00000399249.6 link	c.3535G>A	p.Glu1179Lys	missense_variant	Exon 31 of 34	5		ENSP00000382193.2		A8MXZ9

Frequencies

GnomAD3 genomes

AF:

0.000381

AC:

AN:

152136

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.0164

Gnomad AMR

AF:

0.000458

Gnomad ASJ

AF:

0.00231

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00166

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000235

Gnomad OTH

AF:

0.000956

GnomAD3 exomes

AF:

0.000452

AC:

112

AN:

247566

Hom.:

AF XY:

0.000520

AC XY:

AN XY:

134498

show subpopulations

Gnomad AFR exome

AF:

0.000131

Gnomad AMR exome

AF:

0.000466

Gnomad ASJ exome

AF:

0.00199

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00131

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000286

Gnomad OTH exome

AF:

0.000333

GnomAD4 exome

AF:

0.000265

AC:

387

AN:

1461264

Hom.:

Cov.:

AF XY:

0.000314

AC XY:

228

AN XY:

726918

show subpopulations

Gnomad4 AFR exome

AF:

0.000269

Gnomad4 AMR exome

AF:

0.000515

Gnomad4 ASJ exome

AF:

0.00172

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00145

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000132

Gnomad4 OTH exome

AF:

0.000530

GnomAD4 genome

AF:

0.000381

AC:

AN:

152254

Hom.:

Cov.:

AF XY:

0.000430

AC XY:

AN XY:

74458

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.000457

Gnomad4 ASJ

AF:

0.00231

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00166

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000235

Gnomad4 OTH

AF:

0.000946

Alfa

AF:

0.000253

Hom.:

Bravo

AF:

0.000476

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000727

AC:

ExAC

AF:

0.000405

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.000164

EpiControl

AF:

0.000178

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5Benign:12Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:3

Jun 24, 2013

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

- -

Nov 04, 2016

Stanford Center for Inherited Cardiovascular Disease, Stanford University

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: provider interpretation

Based on this variant's presence in individuals with another disease-causing variant, and the frequency of this variant in the general population, including individuals of Ashkenazi Jewish descent (this patient's ethnicity), we classify this variant as likely benign and do not feel it is suitable for testing family members ("predictive genetic testing"). In total the variant has been seen in at least 12 seemingly unrelated cases of cardiac disease, mostly cardiomyopathy (not including the patient). However many of these individuals had another variant and, in addition, p.Glu1179Lys has also been observed at a higher than expected frequency in individuals from the general population. There is no segregation data available. ClinVar submissions include: variant of uncertain significance (LMM, GeneDx, CHEO, ClinSeq) and likely benign (Invitae). GeneDx notes that they have identified this variant in two other unrelated individuals tested for HCM in their lab (one had a disease-causing variant in another gene (not our case)) and one individual they tested for DCM (who also had a disease causing variant in another gene (could be our case, unclear at this time)). GeneDx identified this variant in 2 unaffected siblings of the proband. Segregation data is not available to date. LMM has identified this variant in 4 individuals with HCM, 2 with DCM and one individual with left ventricular dilation. Two of these individuals had variants in other genes that were sufficient to explain their disease. Per their report, "Glutamic acid (Glu) at position 1179 is not conserved in evolutionarily distant species and the change to Lysine (Lys) was predicted to be benign using a computational tool clinically validated by our laboratory. This tool's benign prediction is estimated to be correct 89% of the time (Jordan 2011)." LMM's ClinVar submission notes a classification of variant of uncertain significance (as of March 25th, 2015). The entry notes LMM "has detected this variant in 4 individuals with HCM, 1 individual with LV dilatation, and in 1 individual with DCM." They do not note whether these individuals had other variants. Presumably the individual with left ventricular dilatation is the same case reported in Pugh et al (2014). We have seen p.Glu1179Lys in another patient with HCM, who had only this one variant. We have also seen the variant in a 1yo girl with non-compaction and dilated cardiomyopathy. She also had a variant in DES (not classified by us yet). Rodriguez-Garcia et al (2010) reported the variant in a patient with HCM from their Spanish cohort. Of note, they only reported on MYBPC3 in that paper so it is not known whether the patient had variants in other HCM genes. It appears that Brion et al (2012) may have observed the variant in a SIDS case (with a normal heart), though unfortunately the paper is not available to us. Kassem et al (2012) reported the variant in one of 192 Egyptian patients with HCM. MYBPC3, MYH7, and TNNT2 were sequenced and p.Glu1179Lys was the only variant that patient harbored in those genes. LMM reported a patient with this variant in their DCM series (Pugh et al 2014). The patient was a 32yo Caucasian female with left ventricular dilation and regional wall abnormalities. She underwent a 46 gene cardiomyopathy panel and carried multiple variants of uncertain significance in addition to this one (including variants in ABCC9, CASQ2, DSP). Sabater-Molina et al 2013 note they found this variant in a European cohort (mostly Spanish, but authors not overlapping with Rodriguez-Garcia et al 2010) with various inherited cardiovascular diseases. Unfortunately it is not noted which condition this was observed with, though patients with HCM made up roughly half the cohort. Maron et al (2012) report a "G+LVH-" patient with this variant who has a maximal left ventricular wall thickness of 1.0 cm and had three crypts on imaging. The substitution is chemically conservative and in silico analyses with SIFT -

May 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The MYBPC3 p.Glu1179Lys variant was identified in 3 of 1956 proband chromosomes (frequency: 0.0015) from individuals or families with hypertrophic and dilated cardiomyopathies (Pugh_2014_PMID:24503780; Rodrâˆšâ‰ guez-Garcâˆšâ‰ a_2010_PMID:20433692; Kassem_2012_PMID:23233322). The variant was also identified in dbSNP (ID: rs199669878), ClinVar (classified as a VUS by four laboratories and as likely benign by two laboratories) and LOVD 3.0 (classified as a VUS). The variant was identified in control databases in 115 of 278922 chromosomes at a frequency of 0.000412 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Ashkenazi Jewish in 20 of 10318 chromosomes (freq: 0.001938), South Asian in 40 of 30546 chromosomes (freq: 0.00131), Latino in 16 of 35212 chromosomes (freq: 0.000454), Other in 2 of 7090 chromosomes (freq: 0.000282), European (non-Finnish) in 35 of 127334 chromosomes (freq: 0.000275) and African in 2 of 24006 chromosomes (freq: 0.000083), while the variant was not observed in the East Asian and European (Finnish) populations. The E1179K variant was identified in 1/140 cases of sudden infant death syndrome (Brion_2009). The p.Glu1179 residue is conserved in mammals and 3 of 4 computational analyses (SIFT, AlignGVGD, MutationTaster) suggest that the variant may impact the protein; however this information is not enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

Nov 11, 2020

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 20433692, 25351510, 28771489, 22361390, 22563033, 23233322, 26914223, 22958901, 23861362, 24503780, 28679633, 26367797, no PMID, 28843747, 30972196, 30847666, 31980526) -

not specified

Uncertain:1Benign:2

Sep 24, 2019

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Glu1179Lys variant in MYBPC3 is classified as likely benign because it has been identified in 0.19% (20/10318) of Ashkenazi Jewish and 0.13% (40/30546) of South Asian chromosomes by gnomAD (http://gnomad.broadinstitute.org). Although this variant has been identified in affected individuals (Brion 2009, Rodriquez-Garcia 2010, Kassem 2013, LMM data), the associated phenotypes are variable (including HCM, DCM, and SIDS), and some of these individuals carried variants in other genes sufficient to explain their disease. ACMG/AMP Criteria applied: BA1, PS4_Supporting. -

Jun 24, 2020

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

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: MYBPC3 c.3535G>A (p.Glu1179Lys) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00045 in 247566 control chromosomes, predominantly at a frequency of 0.0013 within the South Asian subpopulation in the gnomAD database. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 1.3 fold of the estimated maximal expected allele frequency for a pathogenic variant in MYBPC3 causing Hypertrophic Cardiomyopathy phenotype (0.001), strongly suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. c.3535G>A has been reported in the literature in multiple individuals affected with Hypertrophic Cardiomyopathy (e.g. Rodriguez-Garcia_2010, Kassem_2013, Garcia-Molina_2019), Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC) (Choung_2017) and Sudden Infant Death (SID) syndrome (Brion_2012). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Ten ClinVar submitters (evaluation after 2014) cite the variant as benign/likely benign (n=4) or uncertain significance (n=6). Two of the ClinVar submitters mention co-occurrences with other pathogenic variants in patients carrying this variant without providing details. Based on the evidence outlined above, the variant was classified as likely benign. -

May 23, 2017

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hypertrophic cardiomyopathy 4

Uncertain:1Benign:1Other:1

Aug 22, 2023

Mendelics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

GenomeConnect, ClinGen

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Cardiomyopathy

Benign:2

Nov 25, 2022

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 16, 2018

Color Diagnostics, LLC DBA Color Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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 16, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Primary dilated cardiomyopathy

Uncertain:1

Genetics and Genomics Program, Sidra Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

- -

Left ventricular noncompaction 10

Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Cardiovascular phenotype

Benign:1

Dec 20, 2021

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.27

CardioboostCm

Uncertain

0.22

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Uncertain

-0.030

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.34

T;T;T

Eigen

Uncertain

0.44

Eigen_PC

Uncertain

0.46

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Pathogenic

0.98

D;D;D

M_CAP

Pathogenic

0.31

MetaRNN

Benign

0.11

T;T;T

MetaSVM

Uncertain

-0.14

MutationAssessor

Pathogenic

3.1

M;.;.

PrimateAI

Uncertain

0.62

PROVEAN

Uncertain

-2.5

N;.;N

REVEL

Uncertain

0.46

Sift

Benign

0.098

T;.;T

Sift4G

Benign

0.12

T;T;T

Vest4

0.91

MVP

0.87

MPC

0.81

ClinPred

0.12

GERP RS

5.1

Varity_R

0.36

gMVP

0.87

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.12

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