NM_000256.3:c.1790G>A

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PP3_StrongPP5_Very_Strong

The NM_000256.3(MYBPC3):c.1790G>A(p.Arg597Gln) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000154 in 1,557,688 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

MYBPC3
NM_000256.3 missense, splice_region

Scores

Splicing: ADA: 1.000

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:13

Conservation

PhyloP100: 7.53

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 14 ACMG points.

PM1

In a domain Ig-like C2-type 4 (size 89) in uniprot entity MYPC3_HUMAN there are 31 pathogenic changes around while only 3 benign (91%) in NM_000256.3

PP3

Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. Scorers claiming Uncertain: max_spliceai. No scorers claiming Benign.

PP5

Variant 11-47341991-C-T is Pathogenic according to our data. Variant chr11-47341991-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 164098.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-47341991-C-T is described in Lovd as [Pathogenic]. Variant chr11-47341991-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYBPC3	NM_000256.3 link	c.1790G>A	p.Arg597Gln	missense_variant, splice_region_variant	Exon 18 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.1790G>A	p.Arg597Gln	missense_variant, splice_region_variant	Exon 18 of 35	5	NM_000256.3	ENSP00000442795.1	Q14896-1
MYBPC3	ENST00000399249.6 link	c.1790G>A	p.Arg597Gln	missense_variant, splice_region_variant	Exon 17 of 34	5		ENSP00000382193.2	A8MXZ9
MYBPC3	ENST00000544791.1 link	n.1790G>A		splice_region_variant, non_coding_transcript_exon_variant	Exon 18 of 27	5		ENSP00000444259.1	F5GZR4

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152202

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000393

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:

0.0000300

AC:

AN:

166884

Hom.:

AF XY:

0.0000227

AC XY:

AN XY:

88090

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000119

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000856

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000121

AC:

AN:

1405486

Hom.:

Cov.:

AF XY:

0.0000115

AC XY:

AN XY:

693736

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000833

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000552

Gnomad4 SAS exome

AF:

0.000100

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000370

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000460

AC:

AN:

152202

Hom.:

Cov.:

AF XY:

0.0000807

AC XY:

AN XY:

74342

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000393

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:

0.0000688

Hom.:

Bravo

AF:

0.0000491

ExAC

AF:

0.00000856

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hypertrophic cardiomyopathy

Pathogenic:5

Aug 21, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 597 of the MYBPC3 protein (p.Arg597Gln). This variant also falls at the last nucleotide of exon 18, which is part of the consensus splice site for this exon. This variant is present in population databases (rs727503195, gnomAD 0.01%). This missense change has been observed in individuals with hypertrophic cardiomyopathy (HCM) (PMID: 23674513, 24111713, 25086479, 27532257, 27600940). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 164098). 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. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this missense change alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 25849606, 28679633). For these reasons, this variant has been classified as Pathogenic. -

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

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Sep 01, 2020

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Arg597Gln variant in MYBPC3 has been identified in at least 15 individuals with hypertrophic cardiomyopathy and segregated with disease in 1 affected relative (Berge 2014, Curila 2012, Chiou 2015, Millat 2015, Walsh 2016, LMM data, GeneDx pers. comm., Ambry pers comm., Invitae pers. comm., Stanford pers. comm., CHEO pers. comm, SHaRe database). The variant has been identified in 5/166884 chromosomes by gnomAD (http://gnomad.broadinstitute.org/). This variant is located in the last three bases of the exon, which is part of the 5' splice region. An in vitro functional study showed that cells harboring this variant produced a shorter mRNA product than wild type cells, consistent with skipping of exon 18 (Millat 2015). Computational tools also suggest some impact to splicing. 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, PS3_Supporting, PP3. -

Sep 02, 2024

All of Us Research Program, National Institutes of Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1790G>A (p.Arg597Gln) variant of the MYBPC3 gene is predicted to replace arginine with glutamine at codon 597 of the MYBPC3 protein. This variant also falls at the last nucleotide of exon 18, which is part of the consensus splice site for this exon. Studies using in vitro hybrid minigene assays suggested aberrant splicing impact from the c.1790G>A variant and an altered mRNA splicing leading to a premature termination codon (PMID: 28679633). This variant has been observed in multiple individuals with hypertrophic cardiomyopathy (HCM) (PMID: 23674513, 24111713, 25086479, 27532257, 27600940, 22455086, 25849606). It has also been observed to segregate with disease in 1 affected relative (PMID: 25086479). This variant has been identified in 5/166884 chromosomes in the general population according to the Genome Aggregation Database (gnomAD). In silico splice site analysis predicts that this alteration may weaken the native splice donor site and may result in the creation or strengthening of a novel splice donor site. Based on these evidence, c.1790G>A (p.Arg597Gln) variant in MYBPC3 gene is interpreted as pathogenic. -

Feb 09, 2017

Center for Human Genetics, University of Leuven

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACMG score pathogenic -

not provided

Pathogenic:3

Oct 28, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Identified in patients with cardiomyopathy referred for genetic testing at GeneDx and in published literature (PMID: 22455086, 23674513, 23508784, 25086479, 24111713, 27600940, 31513939, 31110529, 29255176, 32369506, 34400558, 36291626, 35653365, 36264615, 37652022, 37342443); Published functional studies demonstrate a damaging effect as this variant results in abnormal splicing and skipping of exon 18 in HeLa cells (PMID: 25849606); Not observed at significant frequency in large population cohorts (gnomAD); Located in the last nucleotide position of the exon, which is part of the splice donor site; This variant is associated with the following publications: (PMID: 27532257, 28679633, 31513939, 26553696, 22455086, 31006259, 32824488, 32841044, 31323898, 27600940, 23674513, 23508784, 24111713, 29255176, 34400558, 36291626, 36335097, 34503678, 32369506, 35653365, 31110529, 25086479, 25849606, 35130036, 36264615, 37652022, 36136372, 37342443, 34461741) -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Hypertrophic cardiomyopathy 4

Pathogenic:2

Juno Genomics, Hangzhou Juno Genomics, Inc

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM2_Supporting+PS4_Moderate+PP4+PS3_Moderate -

Mar 29, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiomyopathy

Pathogenic:1

Oct 19, 2021

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

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiovascular phenotype

Pathogenic:1

Sep 23, 2024

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1790G>A variant (also known as p.R597Q), located in coding exon 18 of the MYBPC3 gene, results from a G to A substitution at nucleotide position 1790. The amino acid change results in arginine to glutamine at codon 597, an amino acid with highly similar properties. However, this change occurs in the last base pair of coding exon 18, which makes it likely to have some effect on normal mRNA splicing. This variant also has been reported in hypertrophic cardiomyopathy (HCM) cohorts (Curila K et al. Acta Cardiol. 2012;67:23-9; Berge KE et al. Clin Genet. 2014;86:355-60; Witjas-Paalberends ER et al. Cardiovasc. Res. 2013 Aug;99(3):432-41; Chiou KR et al. J Cardiol. 2015;65:250-6; Walsh R et al. Genet Med. 2017;19:192-203). In one study, an in vitro minigene splicing assay has suggested this variant results in out-of-frame skipping of exon 18 which results in the introduction of a premature truncation codon (Millat G et al. DNA Cell Biol. 2015;34:489-96), and a second minigene assay has also suggested aberrant splicing impact (Ito K. Proc. Natl. Acad. Sci. U.S.A.. 2017 Jul;114(29):7689-7694). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration may weaken the native splice donor site and may result in the creation or strengthening of a novel splice donor site. This amino acid position is highly conserved in available vertebrate species. In addition, as a missense substitution this is predicted to be inconclusive by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

MYBPC3-related cardiomyopathies

Pathogenic:1

May 23, 2020

Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant affects the last nucleotide of exon 18 of MYBPC3 gene and may therefore alter native splicing. This variant has been previously reported as a heterozygous change in patients with hypertrophic cardiomyopathy (PMID: 22455086, 25849606, 25086479, 27532257, 31006259). In-vitro studies in mammalian cells using a mini gene assays have shown that this missense change results in aberrant splicing (PMID: 25849606, 28679633). It is present in the heterozygous state in the gnomAD population database at a frequency of 0.003% (5/166884) and thus is presumed to be rare. The c.1790G>A (p.Arg597Gln) variant is predicted by multiple in silico tools to have a deleterious effect on protein function. Based on the available evidence, the c.1790G>A (p.Arg597Gln) variant is classified as Likely Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

CardioboostCm

Pathogenic

0.92

BayesDel_addAF

Uncertain

0.068

BayesDel_noAF

Uncertain

0.090

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.67

D;T;T

Eigen

Pathogenic

0.80

Eigen_PC

Pathogenic

0.78

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.99

D;D;D

M_CAP

Pathogenic

0.35

MetaRNN

Pathogenic

0.85

D;D;D

MetaSVM

Benign

-0.31

MutationAssessor

Uncertain

2.2

M;.;.

PrimateAI

Uncertain

0.50

PROVEAN

Uncertain

-3.3

D;.;D

REVEL

Uncertain

0.39

Sift

Uncertain

0.019

D;.;D

Sift4G

Uncertain

0.0060

D;D;D

Vest4

0.95

MVP

0.87

MPC

0.88

ClinPred

0.91

GERP RS

5.1

Varity_R

0.51

gMVP

0.78

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.97

SpliceAI score (max)

0.49

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.49

Position offset: 17

DS_DL_spliceai

0.32

Position offset: 0

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