11-47342611-C-T

Position:

chr11-47342611-C-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PS1PM1PP3_StrongPP5

The NM_000256.3(MYBPC3):c.1591G>A(p.Gly531Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000211 in 1,612,338 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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 Pathogenicin Lovd. Synonymous variant affecting the same amino acid position (i.e. G531G) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000021 ( 0 hom. )

Consequence

MYBPC3
NM_000256.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:18U:1

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 Pathogenic. Variant got 11 ACMG points.

PS1

Transcript NM_000256.3 (MYBPC3) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in Lovd

PM1

In a domain Ig-like C2-type 3 (size 90) in uniprot entity MYPC3_HUMAN there are 33 pathogenic changes around while only 9 benign (79%) in NM_000256.3

PP3

MetaRNN computational evidence supports a deleterious effect, 0.964

PP5

Variant 11-47342611-C-T is Pathogenic according to our data. Variant chr11-47342611-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 164109.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=15, Uncertain_significance=1}. Variant chr11-47342611-C-T is described in Lovd as [Likely_pathogenic]. Variant chr11-47342611-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYBPC3	NM_000256.3 linkuse as main transcript	c.1591G>A	p.Gly531Arg	missense_variant	17/35	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.1591G>A	p.Gly531Arg	missense_variant	17/35	5	NM_000256.3	ENSP00000442795	P4	Q14896-1
MYBPC3	ENST00000399249.6 linkuse as main transcript	c.1591G>A	p.Gly531Arg	missense_variant	16/34	5		ENSP00000382193	A2
MYBPC3	ENST00000544791.1 linkuse as main transcript	c.1591G>A	p.Gly531Arg	missense_variant, NMD_transcript_variant	17/27	5		ENSP00000444259

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152208

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

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

GnomAD3 exomes

AF:

0.0000324

AC:

AN:

247086

Hom.:

AF XY:

0.0000298

AC XY:

AN XY:

134034

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000557

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000538

Gnomad OTH exome

AF:

0.000167

GnomAD4 exome

AF:

0.0000205

AC:

AN:

1460130

Hom.:

Cov.:

AF XY:

0.0000220

AC XY:

AN XY:

726248

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000448

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000101

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000198

Gnomad4 OTH exome

AF:

0.0000332

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152208

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74364

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000448

Hom.:

Bravo

AF:

0.0000416

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000595

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:18Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:8

Likely pathogenic, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	May 29, 2016	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jan 04, 2022	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	MYBPC3: PS1, PS4:Moderate, PM2:Supporting, PS3:Supporting -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 11, 2024	Published functional studies suggest a damaging effect in mouse engineered heart tissue (PMID: 27108529); 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: 16858239, 27532257, 20031602, 19150014, 20173211, 20594303, 21750094, 22765922, 23690394, 23508784, 27590665, 28356264, 28193612, 28152038, 28679633, 33673806, 32369506, 35130036, Emrahi2022, 18533079, 36264615, 37652022, 27108529) -
Likely pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Apr 23, 2018	PP3, PM2, PS3_supporting, PS4_moderate -
Likely pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Hypertrophic cardiomyopathy

Pathogenic:4

Likely pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Jun 09, 2024	This missense variant replaces glycine with arginine at codon 531 of the MYBPC3 protein (c.1591G>A; p.Gly531Arg). Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). A functional study has shown that a different nucleotide change with the same protein effect (c.1591G>C; p.Gly531Arg) does not fully rescue the hypercontractile phenotype of heart tissue from Mybpc3 knockout mouse (PMID: 27108529). Considering both c.1591G>A and c.1591G>C nucleotide changes, the p.Gly531Arg missense variant has been reported in over 10 individuals affected with hypertrophic cardiomyopathy (PMID: 16858239, 18533079, 19150014, 20624503, 21750094, 21835320, 22765922, 23508784, 27483260, 27532257, 28356264, 32369506, 33495597, 33673806). Two of these individuals carried a different pathogenic variant in the same gene (PMID: 20624503, 27483260), and one of them showed early-onset of disease before age 25 (PMID: 27483260). This variant has been identified in 8/247086 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 11, 2021	The p.Gly531Arg variant in MYBPC3 has been reported in association with two distinct nucleotide changes: c.1591G>C and c.1591G>A. Considering both nucleotide changes, this variant has been reported in 1 individual with dilated cardiomyopathy (DCM; c.1591G>A; Waldmuller 2011 PMID: 21750094) and in over 10 individuals with hypertrophic cardiomyopathy (HCM; c.1591G>A: Girolami 2006 PMID: 16858239, Olivotto 2008 PMID: 18533079, Garcia-Castro 2009 PMID: 19150014, Michels 2011, Waldmuller 2011 PMID: 21750094, Walsh 2017 PMID: 27532257, LMM data; c.1591G>C: Millat 2010 PMID: 20624503, Olivotto 2011 PMID: 21835320, Coto 2012 PMID: 22765922, Rubattu 2016 PMID: 27483260, LMM data). Of the individuals with HCM, at least 4 individuals carried a second pathogenic MYBPC3 variant and had early onset disease (LMM data, Millat 2010 PMID: 20624503, Rubattu 2016 PMID: 27483260). Furthermore, the c.1591G>C variant was found by our laboratory to segregate with disease in 2 affected relatives from 1 family. This variant has also been reported by other clinical laboratories in ClinVar (Variation IDs: 164109 (c.1591G>A) and 42550 (c.1591G>C)). Additionally, the c.1591G>A variant has been identified in 0.005% (1/17952) of East Asian and in 0.005% (6/111606) of European chromosomes by gnomAD, while the c.1591G>C variant has been identified in 0.003% (4/127020) of European chromosomes and 0.004% (1/24164) of African chromosomes in gnomAD (https://gnomad.broadinstitute.org/). A functional study in which the c.1591G>C (p.Gly531Arg) variant was transfected into MYBPC3 knockout mouse cardiomyocytes alone and in combination with wild-type MYBPC3 (to represent homozygous and heterozygous disease states) revealed abnormal contractile force in both scenarios compared to wild-type (Wijnker 2016 PMID: 27108529). Computational prediction tools and conservation analysis also suggest that the variant may impact the protein. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant HCM. ACMG/AMP Criteria applied: PS4_Moderate, PM2_Supporting, PS3_Moderate, PP3. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	Jun 09, 2023	The c.1591G>A (p.Gly531Arg) variant of the MYBPC3 gene replaces glycine with arginine at codon 531 of the MYBPC3 protein. This variant has been reported in more than 10 unrelated individuals affected with hypertrophic cardiomyopathy (HCM) (PMID: 18533079, 20624503, 21750094, 23508784, 27483260, 27532257, 27600940, 28356264, 33673806, 21835320,33673806). A functional study in which the c.1591G>C (p.Gly531Arg) variant was transfected into MYBPC3 knockout mouse cardiomyocytes alone and in combination with wild-type MYBPC3 (to represent homozygous and heterozygous disease states) revealed abnormal contractile force in both scenarios compared to wild-type (PMID: 27108529). In addition, an alternative nucleotide change resulting in the same protein change (c.1591G>C; p.Gly531Arg) has been classified as likely pathogenic for autosomal dominant HCM by 7 submitters in ClinVar (Variation ID: 42550). Computational evidence supports a deleterious effect on the protein structure and function (REVEL score 0.854). This variant has been identified in 8/247086 chromosomes in the general population (gnomAD). Based on these evidence, the c.1591G>A (p.Gly531Arg) variant of the MYBPC3 gene is interpreted as likely pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 06, 2023	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 531 of the MYBPC3 protein (p.Gly531Arg). This variant is present in population databases (rs397515912, gnomAD 0.006%). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 18533079, 20624503, 21750094, 23508784, 27483260, 27532257, 27600940, 28356264, 33673806). ClinVar contains an entry for this variant (Variation ID: 164109). 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. -

Hypertrophic cardiomyopathy 4

Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Apr 04, 2024	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Oct 08, 2024	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with hypertrophic cardiomyopathy 4 (HCM; MIM#115197). (I) 0108 - This gene is associated with both recessive and dominant disease. Dominant inheritance is frequently reported in adult-onset conditions and recessive inheritance results in a more severe early onset phenotype (OMIM). (I) 0115 - Variants in this gene are known to have variable expressivity (PMID: 32841044). (I) 0200 - Variant is predicted to result in a missense amino acid change from glycine to arginine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2 and v3 (non-v2)) <0.01 (12 heterozygotes, 0 homozygotes). A different nucleotide substitution resulting in the same amino acid change has also been observed in gnomAD (v2 and v3 (non-v2): 8 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v3) (p.(Gly531Trp): 1 heterozygote, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated Immunoglobulin I-set domain (DECIPHER). (I) 0710 - Another missense variant comparable to the one identified in this case has inconclusive previous evidence for pathogenicity. The p.(Gly531Trp) variant has been classified as a VUS by multiple clinical diagnostic laboratories (ClinVar). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant (G>A) and a different nucleotide substitution (G>C), which result in the same amino acid change, have been classified as likely pathogenic and pathogenic by multiple clinical diagnostic laboratories and have been reported in multiple individuals with HCM (ClinVar; Atlas of Cardiac Genetic Variation; PMIDs: 21750094, 24793961, 28356264, 31941943, 32841044, 36291626). Additionally, this amino acid change has also been classified as a VUS by two clinical diagnostic laboratories and has also been reported in one individual with left ventricular noncompaction cardiomyopathy (ClinVar; PMID: 28798025). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Mutant constructs (c.1591G>C; p.(Gly531Arg)) transfected into knockout engineered heart cells mice tissues and expressed either as heterozygous or homozygous demonstrated abnormal force and contraction velocity compared to WT (PMID: 27108529). (SP) 1205 - This variant has been shown to be maternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Likely pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	May 22, 2023	The MYBPC3 c.1591G>A (p.Gly531Arg) missense variant has been reported in two individuals with hypertrophic cardiomyopathy (HCM) and one with dilated cardiomyopathy (PMID: 21750094; 33673806). A c.1591G>C variant, which results in the same amino acid change, has been reported in at least five unrelated individuals with HCM and has been shown to segregate with the disease in the affected child of one proband (PMID: 21835320; 24793961; 25351510; 27532257; doi:10.1016/j.genrep.2021.101471). The c.1591G>C variant has also been reported in two individuals with early-onset disease who carried a second variant in MYBPC3 (PMID: 27483260). In addition, the p.Gly531Arg variant has been identified in at least three additional individuals with HCM without the nucleotide change being specified (PMID: 16858239; 20031602; 22765922). The c.1591G>A variant is not observed at a significant frequency in version 2.1.1 or version 3.1.2 of the Genome Aggregation Database. Multiple lines of computational evidence suggest the variant may have a deleterious effect on the gene or gene product. Functional studies demonstrated that the c.1591G>A (p.Gly531Arg) variant was unable to restore maximal force to the wild-type level when it was co-expressed with the wild-type protein in engineered heart tissue from MYBPC3 knock-out mice (PMID: 27108529). Based on the available evidence, the c.1591G>A (p.Gly531Arg) variant is classified as likely pathogenic for hypertrophic cardiomyopathy. -

Cardiomyopathy

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jan 02, 2024	This missense variant replaces glycine with arginine at codon 531 of the MYBPC3 protein (c.1591G>A; p.Gly531Arg). Computational prediction tools indicate that this variant has a deleterious impact on protein structure and function. A functional study has shown that a different nucleotide change with the same protein effect (c.1591G>C; p.Gly531Arg; ClinVar variation ID: 164109) does not fully rescue the hypercontractile phenotype of heart tissue from Mybpc3 knockout mouse (PMID: 27108529). Considering both c.1591G>A and c.1591G>C nucleotide changes, the p.Gly531Arg missense variant has been reported in over 10 individuals affected with hypertrophic cardiomyopathy (PMID: 16858239, 18533079, 19150014, 20624503, 21750094, 21835320, 22765922, 23508784, 27483260, 27532257, 28356264, 32369506, 33495597, 33673806). Two of these individuals also carried a different pathogenic variant in the same gene (PMID: 20624503, 27483260), and one of them showed early-onset of disease before age 25 (PMID: 27483260). This variant has been identified in 8/247086 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	May 12, 2023	- -

Hypertrophic cardiomyopathy 4;C3715165:Left ventricular noncompaction 10

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Juno Genomics, Hangzhou Juno Genomics, Inc

PM2_Supporting+PS4_Moderate+PP4+PP3_Moderate -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 13, 2022

The c.1591G>A (p.G531R) alteration is located in exon 17 (coding exon 17) of the MYBPC3 gene. This alteration results from a G to A substitution at nucleotide position 1591, causing the glycine (G) at amino acid position 531 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.24

CardioboostCm

Uncertain

0.38

BayesDel_addAF

Pathogenic

0.31

BayesDel_noAF

Pathogenic

0.38

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.78

D;T;T

Eigen

Pathogenic

0.71

Eigen_PC

Uncertain

0.60

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.90

D;D;D

M_CAP

Pathogenic

0.67

MetaRNN

Pathogenic

0.96

D;D;D

MetaSVM

Uncertain

0.53

MutationAssessor

Uncertain

2.5

M;.;.

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.74

PROVEAN

Pathogenic

-7.0

D;D;D

REVEL

Pathogenic

0.85

Sift

Pathogenic

0.0

D;D;D

Sift4G

Pathogenic

0.0

D;D;D

Vest4

0.99

MVP

0.93

MPC

0.91

ClinPred

0.98

GERP RS

4.6

Varity_R

0.61

gMVP

0.84

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