11-47341991-C-T

Position:

• chr11-47341991-C-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1 PP3_Moderate PP5_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

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]

ACMG classification

Verdict is Pathogenic. Variant got 12 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: MetaRNN computational evidence supports a deleterious effect, 0.852
• 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/exons	MANE	Protein	UniProt
MYBPC3	NM_000256.3	c.1790G>A	p.Arg597Gln	missense_variant, splice_region_variant	18/35	ENST00000545968.6	NP_000247.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYBPC3	ENST00000545968.6	c.1790G>A	p.Arg597Gln	missense_variant, splice_region_variant	18/35	5	NM_000256.3	ENSP00000442795.1
MYBPC3	ENST00000399249.6	c.1790G>A	p.Arg597Gln	missense_variant, splice_region_variant	17/34	5		ENSP00000382193.2
MYBPC3	ENST00000544791.1	n.1790G>A		splice_region_variant, non_coding_transcript_exon_variant	18/27	5		ENSP00000444259.1

Frequencies

GnomAD3 genomes AF: 0.0000460 AC: 7 AN: 152202 Hom.: 0 Cov.: 33

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: 5 AN: 166884 Hom.: 0 AF XY: 0.0000227 AC XY: 2 AN XY: 88090

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: 17 AN: 1405486 Hom.: 0 Cov.: 32 AF XY: 0.0000115 AC XY: 8 AN XY: 693736

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: 7 AN: 152202 Hom.: 0 Cov.: 33 AF XY: 0.0000807 AC XY: 6 AN XY: 74342

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.: 0

Bravo AF: 0.0000491

ExAC AF: 0.00000856 AC: 1

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypertrophic cardiomyopathy Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Center for Human Genetics, University of Leuven	Feb 09, 2017	ACMG score pathogenic -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 08, 2024	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. -
Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Sep 02, 2024	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. -
Pathogenic, no assertion criteria provided	research	Zaffran Lab, Genetics of Cardiac Diseases Laboratory, Marseille Medical Genetics	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Sep 01, 2020	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. -

not provided Pathogenic:3

Likely pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 28, 2024	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) -

Hypertrophic cardiomyopathy 4 Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Juno Genomics, Hangzhou Juno Genomics, Inc	-	PM2_Supporting+PS4_Moderate+PP4+PS3_Moderate -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 29, 2024	- -

Cardiomyopathy Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

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

Oct 19, 2021

- -

MYBPC3-related cardiomyopathies Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

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

May 23, 2020

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. -

Cardiovascular phenotype Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 23, 2024

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
CardioboostCm	Pathogenic	0.92
BayesDel_addAF	Uncertain	0.068	T
BayesDel_noAF	Uncertain	0.090
CADD	Pathogenic	35
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	D
LIST_S2	Pathogenic	0.99	D;D;D
M_CAP	Pathogenic	0.35	D
MetaRNN	Pathogenic	0.85	D;D;D
MetaSVM	Benign	-0.31	T
MutationAssessor	Uncertain	2.2	M;.;.
PrimateAI	Uncertain	0.50	T
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	D
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

Other links and lift over

dbSNP: rs727503195; hg19: chr11-47363542;