rs376395543

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_ModeratePP3_StrongPP5_Very_Strong

The NM_000256.3(MYBPC3):c.26-2A>G variant causes a splice acceptor change. The variant allele was found at a frequency of 0.0000392 in 1,581,032 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000041 ( 0 hom. )

Consequence

MYBPC3
NM_000256.3 splice_acceptor

Scores

Splicing: ADA: 1.000

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:29

Conservation

PhyloP100: 5.77

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.

PVS1

Splicing variant, NOT destroyed by nmd, known LOF gene, truncates exone, which is 0.06954248 fraction of the gene. Cryptic splice site detected, with MaxEntScore 6.9, offset of 6, new splice context is: acctggcccttcggtctcAGctt. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in inframe 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 11-47351507-T-C is Pathogenic according to our data. Variant chr11-47351507-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 42644.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-47351507-T-C is described in Lovd as [Likely_pathogenic]. Variant chr11-47351507-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYBPC3	NM_000256.3 linkuse as main transcript	c.26-2A>G		splice_acceptor_variant		ENST00000545968.6

Ensembl

Gene	Transcript	HGVSc	Effect	TSL	MANE	Appris	UniProt
MYBPC3	ENST00000545968.6 linkuse as main transcript	c.26-2A>G	splice_acceptor_variant	5	NM_000256.3	P4	Q14896-1
MYBPC3	ENST00000399249.6 linkuse as main transcript	c.26-2A>G	splice_acceptor_variant	5		A2
MYBPC3	ENST00000544791.1 linkuse as main transcript	c.26-2A>G	splice_acceptor_variant, NMD_transcript_variant	5

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152218

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000268

AC:

AN:

223986

Hom.:

AF XY:

0.0000409

AC XY:

AN XY:

122320

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000306

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000498

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000413

AC:

AN:

1428814

Hom.:

Cov.:

AF XY:

0.0000454

AC XY:

AN XY:

705224

show subpopulations

Gnomad4 AFR exome

AF:

0.0000304

Gnomad4 AMR exome

AF:

0.0000463

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:

0.0000504

Gnomad4 OTH exome

AF:

0.0000170

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152218

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74374

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000113

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000120

AC:

ExAC

AF:

0.0000332

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:29

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:10

Pathogenic, criteria provided, single submitter	clinical testing	Blueprint Genetics	Apr 06, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 04, 2022	PP1_STR, PS4, PVS1_MOD, PM2_SUP -
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	Apr 12, 2023	Canonical splice site variant expected to result in aberrant splicing, although in the absence of functional evidence the actual effect of this sequence change is unknown.; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25525159, 27532257, 25637381, 18957093, 24510615, 29029073, 34542152, 15519027, 22267749, 21750094, 27831900, 23674513, 31447099, 34570182, 33673806, 32686758, 33258288, 34135346, 33087929, 34691145, 35537032) -
Pathogenic, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	Jan 27, 2022	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2023	MYBPC3: PVS1, PM2 -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Hypertrophic cardiomyopathy 4

Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genomics Program, Stanford Medicine	Jun 29, 2021	The c.26-2A>G variant in the MYBPC3gene has been previously reported in many unrelated individuals with hypertrophic cardiomyopathy(Van Driest et al., 2004; Ehlermann et al., 2008; Kapplinger et al., 2014; Walsh et al., 2017), and segregated in 6 affected relatives from a five-generation family with left ventricular non-compaction (Sedaghat-Hamedani et al., 2017). This variant has been identified in6/115,748 European non-Finnish chromosomes(7/255,378 chromosomesoverall)by the Genome Aggregation Database (http://gnomad.broadinstitute.org/). Although this variant has been seen in the general population, its frequency is low enough to be consistent with the prevalence of hypertrophic cardiomyopathy.The c.26-2A>G variant alters the canonical acceptor splice site in intron 1, which is predicted to result in abnormal gene splicing.Heterozygous loss-of-function is an established mechanism of disease for the MYBPC3gene(Helms et al., 2020).These data were assessed using the ACMG/AMP variant interpretation guidelines. In summary, there is sufficient evidence to classify the c.26-2A>G variant as pathogenic for autosomal dominant hypertrophic cardiomyopathy based on the information above. [ACMG evidence codes used: PVS1_Strong; PS4; PM2; PP1] -
Pathogenic, criteria provided, single submitter	research	HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	May 08, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	May 29, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	Nov 07, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Jan 01, 2016	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PS1,PP3. -

Hypertrophic cardiomyopathy 4;C3715165:Left ventricular noncompaction 10

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	New York Genome Center	Sep 16, 2022	The c.26-2A>G variant identified in the MYBPC3 gene has been reported in ClinVar as Pathogenic by multiple submitters (VarID:42644) and has been reported in several individuals affected with hypertrophic cardiomyopathy in the literature [PMID: 15519027, 18957093, 27532257, 33673806,others.] The c.26-2A>G variant is observed in 10 alleles (~0.002% minor allele frequency with 0 homozygotes) in population databases (gnomAD v2.1.1 and v3.1.2,TOPMed Freeze 8), suggesting it is not a common benign variant in the populations represented in those databases. The c.26-2A>G variant in MYBPC3 is located inthe canonical splice acceptor site preceding exon 2 of this 34-exon gene, and is presumed to affect mRNA splicing which might result in exon skipping or full/partial intron retention. Based on available evidence this c.26-2A>G variant identified in MYBPC3 is classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	Mar 30, 2021	MYBPC3 NM_000256.3 exon 2 c.26-2A>G: This variant has been reported in the literature in several individuals with HCM or LVNC, segregating with disease in multiple affected family members within at least two families (Van Driest 2004 PMID:15519027, Ehlermann 2008 PMID:18957093, Page 2012 PMID:22267749, Sedaghat-Hamedani 2017 PMID:29029073, Walsh 2017 PMID:27532257). This variant is present in 0.005% (6/115748) of European alleles in the Genome Aggregation Database http://gnomad.broadinstitute.org/variant/11-47373058-T-C). Please note, disease causing variants may be present in control databases at low frequencies, reflective of the general population, reduced penetrance, and/or variable expressivity. This variant is present in ClinVar, with several labs classifying this variant as pathogenic or likely pathogenic (Variation ID:42644). Evolutionary conservation and computational predictive tools for this variant are limited or unavailable. Of note, this variant alters the consensus splice sequence (+/- 1,2) which is predicted to result in an absent or abnormal protein. Loss of function variants are a known mechanism of disease for this gene (Marston 2009 PMID:19574547). In summary, this variant is classified as pathogenic based on the data above (segregation studies, impact to protein etc.) -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Mar 04, 2022	- -

Left ventricular noncompaction 10

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Apr 26, 2022	PVS1, PM2 -
Likely pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Jan 27, 2022	- -

Cardiomyopathy

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 27, 2023	This variant causes an A to G nucleotide substitution at the -2 position of intron 1 splice acceptor site of the MYBPC3 gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. Although RNA studies have not been reported, this variant is expected to disrupt RNA splicing and result in an absent or non-functional protein product. This variant has been reported in over 20 individuals affected with hypertrophic cardiomyopathy (PMID: 15519027, 18957093, 21750094, 22267749, 23674513, 24510615, 27532257, 27831900) and has been shown to segregate with disease in 4 individuals from 2 families (communication with en external laboratory; ClinVar SCV000059162.6). This variant has been identified in 7/255378 chromosomes 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. -
Pathogenic, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Sep 08, 2021	- -

Hypertrophic cardiomyopathy

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Aug 29, 2019	The c.26-2A>G variant in MYBPC3 has been reported in >10 individuals with HCM, segregated with disease in 4 affected relatives from 3 families, including 1 obligate carrier (Van Driest 2004, Ehlermann 2008, Waldmuller 2011, Page 2012, Kapplinger 2014, LMM unpublished data). It has also been reported in ClinVar (Variation ID 42644), in 7/114350 of European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs376395543), and in 2 unaffected adults (Natarajan 2016, LMM unpublished data). For diseases with clinical variability and reduced penetrance, pathogenic variants may be present at a low frequency in the general population. Finally, this variant occurs in the invariant region (+/- 1,2) of the splice consensus sequence, and the variant is predicted to damage the canonical splice site. Heterozygous splice variants in MYBPC3 are prevalent in cases of HCM. However, an alternate splice site is predicted to occur 6 bps downstream, and, if used, would lead to an in-frame deletion of 2 amino acids, though these computational tools are not predictive enough to suggest this alternative splice site would be use in vivo. In summary, this variant meets criteria to be classified as pathogenic for HCM in an autosomal dominant manner based upon predicted impact to the protein, presence in affected individuals and segregation studies. The ACMG/AMP Criteria applied: PS4; PM4; PP1_Supporting; PM2_Supporting. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 24, 2024	This sequence change affects an acceptor splice site in intron 1 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 present in population databases (rs376395543, gnomAD 0.006%). Disruption of this splice site has been observed in individuals with hypertrophic cardiomyopathy (PMID: 15519027, 18957093, 22267749, 23674513, 24510615, 27532257). ClinVar contains an entry for this variant (Variation ID: 42644). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

MYBPC3-related disorder

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Aug 14, 2023	The MYBPC3 c.26-2A>G variant is predicted to disrupt the AG splice acceptor site and interfere with normal splicing. This variant has been reported in multiple patients with hypertrophic cardiomyopathy (Ehlermann et al. 2008. PubMed ID: 18957093; Witjas-Paalberends et al. 2013. PubMed ID: 23674513; Kapplinger et al. 2014. PubMed ID: 24510615). This variant is reported in 0.0052% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/11-47373058-T-C). Variants that disrupt the consensus splice acceptor site in MYBPC3 are expected to be pathogenic. This variant is interpreted as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	DASA	Mar 05, 2022	The c.26-2A>G variant is located in a canonical splice-site, and it is not predicted the protein reading frame alteration, however, occur in a critical region and the variant disrupts <10% of protein - PVS1_moderate. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 42644; PMID: 15519027; PMID: 18957093; PMID: 23674513; PMID: 24510615; PMID: 22267749; PMID: 27532257) - PS4. The variant is present at low allele frequencies population databases (rs376395543 – gnomAD 0.0002741%; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2_supporting. The variant co-segregated with disease in multiple affected family members (PMID: 18957093; 22267749) - PP1_strong. In summary, the currently available evidence indicates that the variant is pathogenic. -

Primary familial hypertrophic cardiomyopathy

Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

CSER _CC_NCGL, University of Washington

Jun 01, 2014

- -

Intellectual disability

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Institute of Human Genetics, University of Leipzig Medical Center

Aug 03, 2020

The variant c.26-2A>G, p.? was identified in an individual with neurodevelopmental disorder (NDD) and classified as Pathogenic according to ACMG guidelines. Inheritance for this variant was unknown.The variants does not (fully) explain the NDD in this individual -

Cardiovascular phenotype

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 20, 2019

The c.26-2A>G intronic pathogenic mutation results from an A to G substitution two nucleotides upstream from coding exon 2 in the MYBPC3 gene. This mutation has been previously reported in individuals with hypertrophic cardiomyopathy (HCM) and left ventricular non-compaction (LVNC) (Page SP et al. Circ Cardiovasc Genet. 2012;5(2):156-66; Ehlermann P et al. BMC Med Genet. 2008;9:95; Van Driest SL et al. J Am Coll Cardiol. 2004;44(9):1903-10; Sedaghat-Hamedani F et al. Eur. Heart J., 2017 Dec;38:3449-3460; Walsh R et al. Genet. Med., 2017 02;19:192-203). In addition to the clinical data presented in the literature, 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. As such, this alteration is classified as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.0012

BayesDel_noAF

Uncertain

-0.060

Cadd

Pathogenic

Dann

Uncertain

0.98

Eigen

Pathogenic

0.85

Eigen_PC

Uncertain

0.63

FATHMM_MKL

Uncertain

0.95

MutationTaster

Benign

1.0

D;D;D

GERP RS

4.3

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.91

SpliceAI score (max)

0.95

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.89

Position offset: -8

DS_AL_spliceai

0.95

Position offset: -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