rs727503216

Positions:

chr11-47349871-G-A

Variant summary

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

The NM_000256.3(MYBPC3):c.557C>T(p.Pro186Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000496 in 1,611,942 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. P186P) has been classified as Benign.

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000051 ( 0 hom. )

Consequence

MYBPC3
NM_000256.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:10

Conservation

PhyloP100: 6.95

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 1 (size 103) in uniprot entity MYPC3_HUMAN there are 30 pathogenic changes around while only 10 benign (75%) 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.557C>T	p.Pro186Leu	missense_variant	5/35	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.557C>T	p.Pro186Leu	missense_variant	5/35	5	NM_000256.3	ENSP00000442795	P4	Q14896-1
MYBPC3	ENST00000399249.6 linkuse as main transcript	c.557C>T	p.Pro186Leu	missense_variant	5/34	5		ENSP00000382193	A2
MYBPC3	ENST00000544791.1 linkuse as main transcript	c.557C>T	p.Pro186Leu	missense_variant, NMD_transcript_variant	5/27	5		ENSP00000444259

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152222

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000942

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000451

AC:

AN:

243662

Hom.:

AF XY:

0.0000452

AC XY:

AN XY:

132712

show subpopulations

Gnomad AFR exome

AF:

0.000137

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000224

Gnomad SAS exome

AF:

0.0000333

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000362

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000507

AC:

AN:

1459720

Hom.:

Cov.:

AF XY:

0.0000482

AC XY:

AN XY:

726038

show subpopulations

Gnomad4 AFR exome

AF:

0.0000598

Gnomad4 AMR exome

AF:

0.0000225

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000227

Gnomad4 SAS exome

AF:

0.0000349

Gnomad4 FIN exome

AF:

0.0000189

Gnomad4 NFE exome

AF:

0.0000513

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152222

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74360

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000942

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000236

Hom.:

Bravo

AF:

0.0000378

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00

AC:

ExAC

AF:

0.0000414

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000596

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:10

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 04, 2019	The p.Pro186Leu variant in MYBPC3 has been reported in 1 individual with HCM (Millat 2010) and was absent from large population studies. Computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. In summary, the clinical significance of the Pro186Leu variant is uncertain. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Sep 16, 2023	Reported in several patients with cardiomyopathy, however, at least two reported individuals harbor co-occurring likely pathogenic or pathogenic variants that may explain their phenotype (Millat et al., 2010; Walsh et al., 2017; Dal Ferro et al., 2017; Mazzarotto et al., 2018; Yeh et al., 2019); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 27532257, 27600940, 24793961, 28416588, Niyazova2019[article], 31879508, 29875424, 20624503, 34426522, 35653365) -
Uncertain significance, no assertion criteria provided	provider interpretation	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Apr 27, 2016	- p.Pro186Leu (c.557C>T) in the MYBPC3 gene Given the lack of case data we consider this variant to be of unknown significance and we do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). We have seen this variant in 1 patient with HCM. Testing was done at ARUP. Millat et al., 2010 reported the P186L variant in one person with HCM. No additional clinical data was provided. The ARUP lab report notes that the proline at codon 186 is only moderately conserved among species. In silico analysis with SIFT predicts the variant to be damaging, PolyPhen-2 predicts the variant to be possibly damaging, and Mutation Taster predicts it to be disease causing. This variant is listed in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/), which currently includes variant calls on ~64,000 individuals of European, African, Latino and Asian descent (as of 4/27/2016). It was seen in 5 of 52,475 individuals, specifically in 2 of 3866 East Asian individuals, 1 of 3773 African individuals, and 2 of 29,548 non-Finnish European individuals. The average coverage at that site in ExAC is moderate, ranging from 10x with peaks at 15x and 25x. -
Uncertain significance, criteria provided, single submitter	clinical testing	Blueprint Genetics	Sep 11, 2017	- -

Hypertrophic cardiomyopathy

Pathogenic:1Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Nov 02, 2023	This missense variant replaces proline with leucine at codon 186 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 reported for this variant. This variant has been reported in multiple individuals affected with hypertrophic cardiomyopathy (PMID: 20624503, 20800588, 27600940, 27885498, 29875424, 30775854, 32841044, 33495596, ClinVar SCV000925171.1). This variant has been identified in 11/243662 chromosomes in the general population by the Genome Aggregation Database (gnomAD). 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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 24, 2023	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 186 of the MYBPC3 protein (p.Pro186Leu). This variant is present in population databases (rs727503216, gnomAD 0.02%). This missense change has been observed in individuals with hypertrophic cardiomyopathy or dilated cardiomyopathy (PMID: 20624503, 27532257, 28416588, 29875424; Invitae). ClinVar contains an entry for this variant (Variation ID: 164147). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Cardiomyopathy

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Oct 19, 2023	This missense variant replaces proline with leucine at codon 186 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 reported for this variant. This variant has been reported in multiple individuals affected with hypertrophic cardiomyopathy (PMID: 20624503, 20800588, 27600940, 27885498, 29875424, 30775854, 32841044, 33495596, ClinVar SCV000925171.1). This variant has been identified in 11/243662 chromosomes in the general population by the Genome Aggregation Database (gnomAD). 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	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Aug 05, 2021	- -

Primary dilated cardiomyopathy;C4021133:Left ventricular noncompaction cardiomyopathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Petrovsky National Research Centre of Surgery, The Federal Agency for Scientific Organizations

Oct 15, 2020

We observed the c.557C>T (p.P186L) in MYBPC3 gene in a female 30-y.o. proband diagnosed with left ventricular noncompaction and dilated cardiomyopathy. The proband also carried a p.W1214* variant in MYBPC3 gene. The family was unavailable for screening. The frequency of p.P186L genetic variant, according to gnomAD, is 4,514e-5, which makes it rare. According to bioinformatic online resources, the p.P186L genetic variant is probably pathogenic. However, in the absence of familial screening and functional studies we assume that the p.P186L genetic variant could only be classified as a variant of uncertain clinical significance. -

Hypertrophic cardiomyopathy 4

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

May 06, 2021

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3B. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with hypertrophic cardiomyopathy 4 (MIM#115197). (I) 0108 - This gene is associated with both recessive and dominant disease. Heterozygous variants are frequently reported in adult onset conditions, however recessive inheritance results in a more severe early onset phenotype (OMIM). (I) 0200 - Variant is predicted to result in a missense amino acid change from proline to leucine. (I) 0251 - Variant is heterozygous. (I) 0302 - Variant is present in gnomAD <0.001 for a dominant condition (11 heterozygotes, 0 homozygotes). (SP) 0502 - Missense variant with conflicting in silico predictions and/or uninformative conservation. Conflicting in silico and moderate conservation. (I) 0600 - Variant is located in an annotated domain or motif, C1 domain; PMID: 20624503. (I) 0705 - No comparable variants have previous evidence for pathogenicity. (I) 0808 - Previous reports of pathogenicity are conflicting. This variant has been reported as either VUS, likely pathogenic or pathogenic in patients with hypertrophic cardiomyopathy and dilated cardiomyopathy. (ClinVar, Cardiodb, PMID: 20624503, 27600940, 28416588). (I) 0905 - No segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 22, 2022

The p.P186L variant (also known as c.557C>T), located in coding exon 5 of the MYBPC3 gene, results from a C to T substitution at nucleotide position 557. The proline at codon 186 is replaced by leucine, an amino acid with similar properties. This variant has been reported in hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM) cohorts, as well as in an HCM genetic testing cohort; however, clinical details have been limited (Millat G et al. Eur J Med Genet 2010 Jul;53:261-7; Dal Ferro M et al. Heart, 2017 11;103:1704-1710; Walsh R et al. Genet Med, 2017 02;19:192-203; Walsh R et al. Genet. Med., 2017 02;19:192-203; Mazzarotto F et al. Genet. Med., 2019 02;21:284-292). This variant has also been reported in the Framingham Heart Study cohort; however, clinical details were limited (Bick AG et al. Am J Hum Genet, 2012 Sep;91:513-9). This alteration has also been reported in whole exome sequencing cohorts (Retterer K et al. Genet Med, 2016 Jul;18:696-704; Kars ME et al. Proc Natl Acad Sci U S A, 2021 Sep;118:). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.27

CardioboostCm

Benign

0.036

BayesDel_addAF

Benign

-0.040

BayesDel_noAF

Uncertain

0.0

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.27

T;T;T

Eigen

Uncertain

0.42

Eigen_PC

Uncertain

0.44

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.94

D;D;D

M_CAP

Uncertain

0.17

MetaRNN

Uncertain

0.47

T;T;T

MetaSVM

Benign

-0.60

MutationAssessor

Benign

1.2

L;.;.

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.57

PROVEAN

Benign

-2.4

N;N;N

REVEL

Uncertain

0.38

Sift

Benign

0.069

T;T;T

Sift4G

Uncertain

0.038

D;D;D

Polyphen

0.97

D;.;.

Vest4

0.49

MutPred

0.59

Loss of catalytic residue at P186 (P = 0.0236);Loss of catalytic residue at P186 (P = 0.0236);Loss of catalytic residue at P186 (P = 0.0236);

MVP

0.89

MPC

0.79

ClinPred

0.59

GERP RS

4.8

Varity_R

0.18

gMVP

0.55

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

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