rs138753870

Variant names:

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 2P and 13B. PM1BP4_StrongBP6BS1BS2

The NM_000256.3(MYBPC3):c.649A>G(p.Ser217Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00109 in 1,605,074 control chromosomes in the GnomAD database, including 22 homozygotes. 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 0.0011 ( 3 hom., cov: 32)

Exomes 𝑓: 0.0011 ( 19 hom. )

Consequence

MYBPC3
NM_000256.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:1B:13

Conservation

PhyloP100: 4.16

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 Benign. Variant got -11 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

BP4

Computational evidence support a benign effect (MetaRNN=0.009872884).

BP6

Variant 11-47349779-T-C is Benign according to our data. Variant chr11-47349779-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 42780.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Benign=9, Uncertain_significance=1}. Variant chr11-47349779-T-C is described in Lovd as [Pathogenic]. Variant chr11-47349779-T-C is described in Lovd as [Likely_pathogenic]. Variant chr11-47349779-T-C is described in Lovd as [Benign]. Variant chr11-47349779-T-C is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0011 (167/152378) while in subpopulation SAS AF= 0.0106 (51/4832). AF 95% confidence interval is 0.00825. There are 3 homozygotes in gnomad4. There are 97 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 3 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYBPC3	NM_000256.3 link	c.649A>G	p.Ser217Gly	missense_variant	Exon 5 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.649A>G	p.Ser217Gly	missense_variant	Exon 5 of 35	5	NM_000256.3	ENSP00000442795.1	Q14896-1
MYBPC3	ENST00000399249.6 link	c.649A>G	p.Ser217Gly	missense_variant	Exon 5 of 34	5		ENSP00000382193.2	A8MXZ9
MYBPC3	ENST00000544791.1 link	n.649A>G		non_coding_transcript_exon_variant	Exon 5 of 27	5		ENSP00000444259.1	F5GZR4

Frequencies

GnomAD3 genomes

AF:

0.00110

AC:

168

AN:

152260

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000265

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00124

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0105

Gnomad FIN

AF:

0.000188

Gnomad MID

AF:

0.0190

Gnomad NFE

AF:

0.00110

Gnomad OTH

AF:

0.00191

GnomAD3 exomes

AF:

0.00186

AC:

447

AN:

240264

Hom.:

AF XY:

0.00245

AC XY:

321

AN XY:

131232

show subpopulations

Gnomad AFR exome

AF:

0.000133

Gnomad AMR exome

AF:

0.000146

Gnomad ASJ exome

AF:

0.000202

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0107

Gnomad FIN exome

AF:

0.000193

Gnomad NFE exome

AF:

0.000907

Gnomad OTH exome

AF:

0.00151

GnomAD4 exome

AF:

0.00109

AC:

1588

AN:

1452696

Hom.:

Cov.:

AF XY:

0.00145

AC XY:

1045

AN XY:

722992

show subpopulations

Gnomad4 AFR exome

AF:

0.0000598

Gnomad4 AMR exome

AF:

0.000202

Gnomad4 ASJ exome

AF:

0.000115

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0107

Gnomad4 FIN exome

AF:

0.000286

Gnomad4 NFE exome

AF:

0.000485

Gnomad4 OTH exome

AF:

0.000962

GnomAD4 genome

AF:

0.00110

AC:

167

AN:

152378

Hom.:

Cov.:

AF XY:

0.00130

AC XY:

AN XY:

74514

show subpopulations

Gnomad4 AFR

AF:

0.000264

Gnomad4 AMR

AF:

0.00124

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.0106

Gnomad4 FIN

AF:

0.000188

Gnomad4 NFE

AF:

0.00112

Gnomad4 OTH

AF:

0.00189

Alfa

AF:

0.000804

Hom.:

Bravo

AF:

0.000786

ESP6500AA

AF:

0.000482

AC:

ESP6500EA

AF:

0.00119

AC:

ExAC

AF:

0.00209

AC:

253

Asia WGS

AF:

0.00346

AC:

AN:

3478

EpiCase

AF:

0.00136

EpiControl

AF:

0.00142

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:1Benign:13

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:4

Dec 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

MYBPC3: BP4, BS1, BS2 -

Jun 24, 2013

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: research

- -

Sep 20, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Reported in ClinVar as a benign and likely benign variant by other clinical laboratories (ClinVar Variant ID# 42780; Landrum et al., 2016); 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: 22763267, 19632136, 23299917, 22464770, 24503780, 25524337, 24119082, 22958901, 22361390, 21750094, 25351510, 26656175, 27650965, 27600940, 28416588, 29121657, 29032884) -

Mar 01, 2016

Stanford Center for Inherited Cardiovascular Disease, Stanford University

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: provider interpretation

reclassified based on 2015 re-review. Data from that re-review is summarized in DOI: 10.1161/CIRCGENETICS.116.001700. -

Hypertrophic cardiomyopathy

Pathogenic:1Benign:2

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Zaffran Lab, Genetics of Cardiac Diseases Laboratory, Marseille Medical Genetics

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Oct 10, 2022

Cohesion Phenomics

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not specified

Benign:3

Feb 23, 2017

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 20, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

p.Ser217Gly in exon 5 of MYBPC3: This variant is not expected to have clinical s ignificance because it has been identified in 1.2% (177/14558) of South Asian ch romosomes, including 4 homozygotes, by the Exome Aggregation Consortium (ExAC, h ttp://exac.broadinstitute.org; dbSNP rs138753870). -

Nov 26, 2019

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.649A>G (p.Ser217Gly) results in a non-conservative amino acid change located in the Immunoglobulin-like domain (IPR007110) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0019 in 240264 control chromosomes, predominantly at a frequency of 0.011 within the South Asian subpopulation in the gnomAD database, including 4 homozygotes. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 10 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 South Asian origin. c.649A>G has been reported in the literature in individuals affected with affected with hypertrophic- or dilated cardiomyopathy, however without strong evidence for causality (e.g. Roberts_2009, Millat_2010, Ogorodnikova_2011, Mestroni_2010, Lakdawala_2012, Merlo_2013, Pugh_2014). These reports do not provide unequivocal conclusions about association of the variant with Cardiomyopathy. Additionally, Lakdawala_2012 reported that this variant did not segregate with the disease in one family. Co-occurrences with other pathogenic variants have been reported (MYBPC3 c.2827C>T (p.Arg943X) in an internal sample; MYH7 c.1357C>T, (p.Arg453Cys) in Roberts_2009), providing supporting evidence for a benign role. Seven ClinVar submitters (evaluation after 2014) cite the variant as benign (5x) and likely benign (2x). Based on the evidence outlined above, the variant was classified as benign. -

Hypertrophic cardiomyopathy 4

Uncertain:1

Jun 04, 2018

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). 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. -

Left ventricular noncompaction 10

Benign:1

Jun 04, 2018

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. -

Cardiomyopathy

Benign:1

Mar 07, 2018

Color Diagnostics, LLC DBA Color Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Long QT syndrome

Benign:1

Jan 08, 2024

Dept of Medical Biology, Uskudar University

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: research

Criteria: BS1, BS2, PP3 -

Cardiovascular phenotype

Benign:1

May 17, 2016

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as 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

0.14

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.37

CADD

Benign

DANN

Uncertain

0.97

DEOGEN2

Benign

0.36

T;T;T

Eigen

Benign

0.018

Eigen_PC

Benign

-0.017

FATHMM_MKL

Uncertain

0.97

LIST_S2

Benign

0.83

T;T;T

MetaRNN

Benign

0.0099

T;T;T

MetaSVM

Benign

-0.45

MutationAssessor

Benign

1.8

L;.;.

PrimateAI

Benign

0.45

PROVEAN

Uncertain

-2.7

D;D;D

REVEL

Uncertain

0.32

Sift

Uncertain

0.0040

D;D;D

Sift4G

Benign

0.066

T;T;T

Polyphen

0.91

P;.;.

Vest4

0.28

MVP

0.86

MPC

0.20

ClinPred

0.064

GERP RS

3.7

Varity_R

0.32

gMVP

0.67

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