rs397515937

Positions:

• chr11-47339792-T-C

Variant summary

Our verdict is Pathogenic. Variant got 20 ACMG points: 20P and 0B. PVS1 PP3_Strong PP5_Very_Strong

The NM_000256.3(MYBPC3):​c.1928-2A>G variant causes a splice acceptor change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000137 in 1,460,836 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: MYBPC3 NM_000256.3 splice_acceptor
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:20
• Conservation: PhyloP100: 7.47

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 20 ACMG points.

• PVS1: Splicing variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 11-47339792-T-C is Pathogenic according to our data. Variant chr11-47339792-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 42585.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-47339792-T-C is described in Lovd as [Likely_pathogenic]. Variant chr11-47339792-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYBPC3	NM_000256.3	c.1928-2A>G		splice_acceptor_variant		ENST00000545968.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYBPC3	ENST00000545968.6	c.1928-2A>G		splice_acceptor_variant		5	NM_000256.3	P4
MYBPC3	ENST00000399249.6	c.1928-2A>G		splice_acceptor_variant		5		A2
MYBPC3	ENST00000544791.1	c.1928-2A>G		splice_acceptor_variant, NMD_transcript_variant		5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.0000137 AC: 20 AN: 1460836 Hom.: 0 Cov.: 31 AF XY: 0.00000826 AC XY: 6 AN XY: 726538

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000171

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000586 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:20

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypertrophic cardiomyopathy Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Center for Human Genetics, University of Leuven	Oct 31, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Aug 14, 2019	The c.1928-2A>G variant in MYBPC3 has been identified in >40 individuals with hypertrophic cardiomyopathy (HCM) and segregated with disease in >20 affected relatives across several families (Bonne 1995, Charron 1998, Erdmann 2001, Richard 2003, Fokstuen 2008, Millat 2010, Teirlinck 2012, Valente 2013, Kapplinger 2014, LMM data). It has also been reported by other clinical laboratories in ClinVar (Variation ID:42585) and was absent from large population studies. This variant occurs in the invariant region (+/- 1,2) of the splice consensus sequence and has been shown to lead to aberrant splicing and subsequently a premature stop codon at position 661 (Bonne 1995, Flavigny 1999, Erdmann 2001). Please note that alternate nomenclature was used in some studies (Charron 1998: SAS int20; Richard 2003: IVS21-2A>G; Erdmann 2001: IVS20-2A>G). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant HCM. ACMG/AMP criteria applied: PS4, PP1_Strong, PM2, PS3. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 26, 2024	This sequence change affects an acceptor splice site in intron 20 of the MYBPC3 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in MYBPC3 are known to be pathogenic (PMID: 19574547). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 7493026, 11499719, 12707239, 18409188, 20439259, 20624503, 23140321, 23690394, 24510615). ClinVar contains an entry for this variant (Variation ID: 42585). Studies have shown that disruption of this splice site alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 10610770, 11499719, 25031304). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Molecular Genetics, Royal Melbourne Hospital	Aug 01, 2023	This sequence change in MYBPC3 occurs within the canonical splice acceptor site of intron 20. It is predicted to cause cryptic acceptor activation resulting in an 11bp deletion in exon 21 leading to premature termination codon and nonsense-mediated decay in a gene in which loss-of-function is an established disease mechanism. This prediction is confirmed by RT-PCR in patient cells (PMID: 7493026, 25031304). An assay also detected intron 20 inclusion predicting a premature termination codon introduced in intron 20 resulting in the disruption in the production of the MYBPC3 protein (PMID: 25031304). This variant is absent from the population database gnomAD v2.1 and v3.1. This variant has been reported in multiple unrelated individuals with hypertrophic cardiomyopathy (PMID: 23140321, 7493026, 12707239, 24510615, 9503187, 11499719, 20439259). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.6.1, this variant is classified as PATHOGENIC. Following criteria are met: PVS1, PS4, PM2_Supporting. -
Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Jan 08, 2024	The c.1928-2A>G variant of the MYBPC3 gene is predicted to disrupt the acceptor splice site in intron 20, resulting in abnormal RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547). Loss-of-function variants in MYBPC3 are known to be pathogenic (PMID: 19574547). This variant was first reported in two large French kindreds with hypertrophic cardiomyopathy (HCM) (PMID: 7493026) and has since then been reported in multiple unrelated individuals and families with HCM (PMID: 11499719, 12707239, 18409188, 20439259, 20624503, 23140321, 23690394, 24510615). This variant has been shown to lead to abnormal mRNA splicing and result in loss of protein expression (PMID: 10610770, 11499719, 25031304). This variant is absent in the general population (gnomAD). Based on these evidence, the c.1928-2A>G variant in MYBPC3 is classified as pathogenic. -
Pathogenic, no assertion criteria provided	research	Agnes Ginges Centre for Molecular Cardiology, Centenary Institute	Dec 11, 2019	The MYBPC3 c.1928-2A>G variant has been identified in numerous HCM probands and has been shown to segregate with disease across several reported families (see references). This variant occurs at the canonical acceptor splice site of intron 20 and leads to aberrant splicing and subsequently a premature stop codon (Bonne G., et al 1995; Flavigny J., et al 1999; Erdmann J., et al 2001; Helms AS, et al., 2010). This variant is absent in the Genome Aggregation Database (http://gnomad.broadinstitute.org/). We have identified this variant in 9 HCM probands. Based on the adapted ACMG guidelines (Kelly MA, et al., 2018) this variant results in loss of function of MYBPC3 (PVS1), has been reported in more than 15 HCM probands (PS4), segregated in multiple families (PP1_Strong) and is rare in the general population (PM2), therefore we classify MYBPC3 c.1928A>G as 'Pathogenic'. -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2022	MYBPC3: PVS1, PM2 -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 06, 2021	Not observed at significant frequency in large population cohorts (gnomAD); Canonical splice site variant in a gene for which loss-of-function is a known mechanism of disease; mRNA functional studies have demonstrated this variant leads to aberrant gene splicing and the introduction of a premature stop codon (Bonne et al., 1995; Erdmann et al., 2001; Helms et al., 2014); Multiple other splice site variants in the MYBPC3 gene have been reported in the Human Gene Mutation Database in association with HCM (HGMD); Reported in ClinVar as pathogenic (ClinVar Variant ID# 42585; ClinVar); This variant is associated with the following publications: (PMID: 25031304, 20439259, 10610770, 28597742, 20624503, 24865491, 12707239, 9503187, 18409188, 23140321, 23348723, 25525159, 25611685, 23690394, 26743238, 26914223, 27532257, 28822653, 28369730, 24510615, 28790153, 25351510, 30128729, 31006259, 30550750, 31447099, 27688314, 31513939, 11499719, 7493026, 31737537, 33954932) -

Hypertrophic cardiomyopathy 4 Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Center of Genomic medicine, Geneva, University Hospital of Geneva	Jul 06, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Medical Genetics Ghent, University of Ghent	Feb 09, 2016	This variant has not been identified in large population databases (Gnomad, 1000 Genomes, Go NL, Exome Variant Server) and is predicted to have an impact on protein function according to multiple prediction programs. In addition, the variant has been reported previously in individuals with cardiomyopathy. The c.1928-2 A>G variant affects the canonical splice acceptor site of intron 20 and leads to aberrant gene splicing and the introduction of a premature stop codon (PMID: 11499719; PMID: 7493026; PMID: 25031304). -
Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 01, 1995	- -

Primary familial hypertrophic cardiomyopathy Pathogenic:3

Pathogenic, no assertion criteria provided	clinical testing	Blueprint Genetics	Oct 07, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 23, 2024	Variant summary: MYBPC3 c.1928-2A>G is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Publications report experimental evidence that this variant affects mRNA splicing (Erdmann_2001, Bonne_1995). The variant was absent in 248758 control chromosomes. c.1928-2A>G has been reported in the literature in numerous individuals and families affected with Hypertrophic Cardiomyopathy (ie. Erdmann_2001, Bonne_1995, Fokstuen_MYH7_2008. ClinVar contains an entry for this variant (Variation ID: 42585). Based on the evidence outlined above, the variant was classified as pathogenic. -

Cardiomyopathy Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	May 18, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 08, 2023	This variant causes an A to G nucleotide substitution at the -2 position of intron 20 of the MYBPC3 gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. RNA studies have confirmed that this variant causes aberrant splicing and is expected to result in an absent or disrupted protein product (PMID: 11499719, 25031304). This variant has been reported in over 30 individuals affected with hypertrophic cardiomyopathy (PMID: 7493026, 11499719, 18409188, 20439259, 20624503, 23140321, 23690394, 24510615, 28615295). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of MYBPC3 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. -

Hypertrophic cardiomyopathy 4;C3715165:Left ventricular noncompaction 10 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

May 18, 2017

- -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

May 25, 2023

The c.1928-2A>G intronic variant results from an A to G substitution two nucleotides before coding exon 21 of the MYBPC3 gene. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This alteration was first reported in two large French kindreds with hypertrophic cardiomyopathy (HCM) (Bonne, 1995), and has since been reported in multiple unrelated individuals and families with HCM (Charron, 1998 (reported as SAS int20); Richard, 2003 (reported as IVS21-2A>G); Teirlinck, 2012 (reported as IVS202A>G); Kapplinger, 2014). This alteration has been shown to lead to abnormal splicing resulting in aberrant protein product (Bonne, 1995; Erdmann, 2001). In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site and will result in the creation or strengthening of a novel splice acceptor site. Based on the available evidence, this alteration is classified as pathogenic. -

MYBPC3-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Aug 14, 2018

The MYBPC3 c.1928-2A>G variant occurs in a canonical splice site (acceptor) and is therefore predicted to disrupt or distort the normal gene product. The c.1928-2A>G variant has not been observed in individuals with either autosomal dominant dilated cardiomyopathy or left ventricular noncompaction cardiomyopathy. Across a selection of the available literature, the c.1928-2A>G variant has been identified in a heterozygous state in 28 families in which it was found in 82 individuals affected with hypertrophic cardiomyopathy, of whom up to 35 individuals are related, in five individuals with an unknown diagnosis or discrete signs of disease, and in six healthy carriers (Bonne et al. 1995; Charron et al. 1998; Erdmann et al. 2001; Richard et al. 2003; Teirlinck et al. 2012). The c.1928-2A>G variant was shown to segregate with disease in two four-generation French families and in a further 13 families of European origin (Bonne et al. 1995; Richard et al. 2003). One of the studies calculated disease penetrance to be 69% and described the variant as being associated with a mild ventricular hypertrophy (Charron et al. 1998). The c.1928-2A>G variant was absent from 600 control chromosomes and is not found in the 1000 Genomes Project, the Exome Sequencing Project, Exome Aggregation Consortium or the Genome Aggregation Database in a region of good sequence coverage so the variant is presumed to be rare. Analysis of MYBPC3 mRNA from patient lymphoblastoid cell lines showed that the c.1928-2A>G variant results in aberrant splicing, causing the skipping of exon 21 and a frameshift with the introduction of a premature stop codon after amino acid residue 661 (Bonne et al. 1995). Expression of the c.1928-2A>G variant in COS-7 cells revealed accumulation to a level similar to wild type, while in fetal rat cardiomyocytes, the variant accumulated to a level that was approximately two-thirds of wild type. Eleven percent of fetal rat cardiomyocyte cells expressing the variant localized correctly in double stripes in the A-band of the sarcomere, but in a more diffuse pattern compared to wild type (Flavigny et al. 1999). Based on the collective evidence and due to the potential impact of splice acceptor variants, the c.1928-2A>G variant is classified as pathogenic for MYBPC3-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.14
CADD	Pathogenic	35
DANN	Uncertain	0.99
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	0.97	D
MutationTaster	Benign	1.0	D;D;D
GERP RS		4.9

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
SpliceAI score (max)		1.0		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.93		Position offset: -13
DS_AL_spliceai		1.0		Position offset: -2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs397515937; hg19: chr11-47361343;