11-47342683-C-T

Position:

chr11-47342683-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 3P and 5B. PM1PP3BP4_StrongBP6

The NM_000256.3(MYBPC3):c.1519G>A(p.Gly507Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000583 in 1,614,008 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Uncertain significancein ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G507V) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0017 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00047 ( 1 hom. )

Consequence

MYBPC3
NM_000256.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:15

Conservation

PhyloP100: 7.50

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 -2 ACMG points.

PM1

In a domain Ig-like C2-type 3 (size 90) in uniprot entity MYPC3_HUMAN there are 51 pathogenic changes around while only 13 benign (80%) in NM_000256.3

PP3

Multiple lines of computational evidence support a deleterious effect 8: BayesDel_noAF, Cadd, Dann, Eigen, M_CAP, MutationAssessor, PROVEAN, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]

BP4

Computational evidence support a benign effect (MetaRNN=0.042181134).

BP6

Variant 11-47342683-C-T is Benign according to our data. Variant chr11-47342683-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 42543.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=9, Benign=6, Uncertain_significance=1}. Variant chr11-47342683-C-T is described in Lovd as [Likely_benign]. Variant chr11-47342683-C-T is described in Lovd as [Pathogenic]. Variant chr11-47342683-C-T is described in Lovd as [Benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYBPC3	NM_000256.3 linkuse as main transcript	c.1519G>A	p.Gly507Arg	missense_variant	17/35	ENST00000545968.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYBPC3	ENST00000545968.6 linkuse as main transcript	c.1519G>A	p.Gly507Arg	missense_variant	17/35	5	NM_000256.3	P4	Q14896-1
MYBPC3	ENST00000399249.6 linkuse as main transcript	c.1519G>A	p.Gly507Arg	missense_variant	16/34	5		A2
MYBPC3	ENST00000544791.1 linkuse as main transcript	c.1519G>A	p.Gly507Arg	missense_variant, NMD_transcript_variant	17/27	5

Frequencies

GnomAD3 genomes

AF:

0.00168

AC:

255

AN:

152192

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00524

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000523

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00173

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000220

Gnomad OTH

AF:

0.00287

GnomAD3 exomes

AF:

0.000598

AC:

149

AN:

249266

Hom.:

AF XY:

0.000481

AC XY:

AN XY:

135218

show subpopulations

Gnomad AFR exome

AF:

0.00535

Gnomad AMR exome

AF:

0.000377

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00161

Gnomad SAS exome

AF:

0.0000654

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000159

Gnomad OTH exome

AF:

0.000661

GnomAD4 exome

AF:

0.000470

AC:

687

AN:

1461698

Hom.:

Cov.:

AF XY:

0.000441

AC XY:

321

AN XY:

727134

show subpopulations

Gnomad4 AFR exome

AF:

0.00553

Gnomad4 AMR exome

AF:

0.000335

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00131

Gnomad4 SAS exome

AF:

0.000139

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000342

Gnomad4 OTH exome

AF:

0.000696

GnomAD4 genome

AF:

0.00167

AC:

254

AN:

152310

Hom.:

Cov.:

AF XY:

0.00157

AC XY:

117

AN XY:

74478

show subpopulations

Gnomad4 AFR

AF:

0.00524

Gnomad4 AMR

AF:

0.000523

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00135

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000221

Gnomad4 OTH

AF:

0.00284

Alfa

AF:

0.000359

Hom.:

Bravo

AF:

0.00201

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00323

AC:

ESP6500EA

AF:

0.000351

AC:

ExAC

AF:

0.000676

AC:

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.000164

EpiControl

AF:

0.000178

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:15

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Benign:5

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 07, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 11, 2024	Variant summary: MYBPC3 c.1519G>A (p.Gly507Arg) results in a non-conservative amino acid change located in the third immunoglobulin subtype 2 domain (IPR003598) of the encoded protein sequence. Four of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00058 in 1607036 control chromosomes, predominantly at a frequency of 0.0054 within the African or African-American subpopulation in the gnomAD database (v4.0 dataset), including 1 homozygote. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 5.4 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. c.1519G>A has been reported in the literature in sequencing studies of individuals affected with and/or undergoing multigene panel testing for Hypertrophic Cardiomyopathy (e.g. Erdmann_2003, Kassem_2013, Lakdawala_2012, Liu_2015). These reports do not provide unequivocal conclusions about association of the variant with Hypertrophic Cardiomyopathy. At-least two co-occurrences with other pathogenic variants have been observed at our laboratory (HCM-MYBPC3 c.2308G>A, p.Asp770Asn; Transthyretin Amylidosis-TTR c.424G>A, p.Val142Ile), providing supporting evidence for a benign role. At least one publication reports experimental evidence evaluating an impact on protein function and demonstrated that the variant didn't destabilize protein structure in an in vitro assay (Suay-Corredera_2021). The following publications have been ascertained in the context of this evaluation (PMID: 23217326, 26332594, 23820649, 22995991, 22763267, 24055113, 12974739, 23233322, 22464770, 26090888, 34097875). ClinVar contains an entry for this variant (Variation ID: 42543). Based on the evidence outlined above, the variant was classified as benign. -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 12, 2015	p.Gly507Arg in exon 17 of MYBPC3: This variant is not expected to have clinical significance because it has been identified in 0.6% (54/9808) of African chromos omes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs35736435). -
Likely benign, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	Jul 12, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Hypertrophic cardiomyopathy 4

Uncertain:1Benign:1

Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Uncertain significance, criteria provided, single submitter	reference population	Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center	Mar 18, 2016	- -

Cardiomyopathy

Benign:2

Benign, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Dec 14, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Apr 13, 2018	- -

not provided

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 15, 2021	This variant is associated with the following publications: (PMID: 23299917, 12974739, 21310275, 15519027, 17560888, 23217326, 22763267, 23233322, 25637381, 22995991, 24055113, 23820649, 26332594, 30188508) -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Mar 28, 2023	- -

Hypertrophic cardiomyopathy

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Feb 05, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -

Primary familial hypertrophic cardiomyopathy

Benign:1

Likely benign, criteria provided, single submitter

research

CSER _CC_NCGL, University of Washington

Jun 01, 2014

- -

Cardiovascular phenotype

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 01, 2018

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. -

Familial amyloid neuropathy

Benign:1

Benign, criteria provided, single submitter

clinical testing

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

May 20, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.39

CardioboostCm

Uncertain

0.17

BayesDel_addAF

Uncertain

0.057

BayesDel_noAF

Pathogenic

0.31

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.77

D;T;T

Eigen

Pathogenic

0.76

Eigen_PC

Pathogenic

0.67

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Pathogenic

0.99

D;D;D

M_CAP

Pathogenic

0.81

MetaRNN

Benign

0.042

T;T;T

MetaSVM

Uncertain

0.49

MutationAssessor

Pathogenic

3.2

M;.;.

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.65

PROVEAN

Pathogenic

-6.9

D;.;D

REVEL

Pathogenic

0.86

Sift

Pathogenic

0.0

D;.;D

Sift4G

Uncertain

0.0020

D;D;D

Vest4

0.88

MVP

0.93

MPC

0.91

ClinPred

0.063

GERP RS

4.6

Varity_R

0.73

gMVP

0.81

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