Variant rs397516082 details in Genebe, Genetics Data Aggregator

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:

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 3.9, offset of -19, new splice context is: agtcttgcccccggccacAGcct. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 11-47346372-T-C is Pathogenic according to our data. Variant chr11-47346372-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 42806.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-47346372-T-C is described in Lovd as [Pathogenic]. Variant chr11-47346372-T-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYBPC3	NM_000256.3 link	c.927-2A>G		splice_acceptor_variant, intron_variant		ENST00000545968.6	NP_000247.2	Q14896-1A5YM48

Ensembl

Gene	Transcript	HGVSc	Effect	TSL	MANE	Protein	UniProt
MYBPC3	ENST00000545968.6 link	c.927-2A>G	splice_acceptor_variant, intron_variant	5	NM_000256.3	ENSP00000442795.1	Q14896-1
MYBPC3	ENST00000399249.6 link	c.927-2A>G	splice_acceptor_variant, intron_variant	5		ENSP00000382193.2	A8MXZ9
MYBPC3	ENST00000544791.1 link	n.927-2A>G	splice_acceptor_variant, intron_variant	5		ENSP00000444259.1	F5GZR4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000508

AC:

AN:

196860

Hom.:

AF XY:

0.00

AC XY:

AN XY:

105782

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000116

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000281

AC:

AN:

1424614

Hom.:

Cov.:

AF XY:

0.00000284

AC XY:

AN XY:

704684

show subpopulations

Gnomad4 AFR exome

AF:

0.00

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:

0.00000366

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000371

Hom.:

Bravo

AF:

0.00000756

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:21

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:9

Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	Jul 13, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	MYBPC3: PVS1, PM2, PS4:Moderate -
Pathogenic, no assertion criteria provided	clinical testing	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Jul 18, 2014	Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. MYBPC3 IVS11-2A>G Based on the data reviewed below, we consider this variant very likely disease causing. This variant has been seen in at least 7 unrelated published HCM cases, with strong segregation data. It was initially reported in 2 presumably unrelated French families with strong segregation data (Bonne et al 1995). All nine individuals with HCM in one family had the variant as did all 20 individuals with HCM in the other family. Christiaans et al (2010) also report at least one family with HCM and this variant (unclear if more than one or how many affected). Ehlermann et al (2008) also reported the variant in two family members with HCM. The London group included two patients with this variant in a study of cardiac phenotype in "G+LVH-" cases from their cohort (Captur et al 2014). They did not note if a family member had HCM and the variant. The variant has also likely been seen in three additional cases. The nomenclature used in these publications differs, which may be due to a difference in the exon and intron numbering scheme. Niimura et al (1998) found “Int12ASA-2G” in two families, with a total 11 individuals who were genotype and phenotype positive. Richard et al (2003) identified “IVS12–2:a7308g” in one index patient. Bonne et al (1995) sequenced mRNA from affected family members with this variant and found evidence of aberrant splicing with two mRNAs of abnormal length. One of these included a shift in frame and a resulting premature stop codon. Many other splice variants in MYBPC3 have been implicated in HCM: IVS2-1G>A, IVS6-2A>C, IVS7+1G>A, IVS8+1G>A, IVS8+5G>A, IVS12-2A>G, IVS16-1G>A, IVS15-13G>A, IVS14-2A>G, IVS18+2T>C, IVS20-2A>G, IVS21-2A>G, IVS22+2T>G, IVS22+1G>A, IVS23-2delA, IVS24+1G>A, IVS24+1G>T, IVS24-26A>G, IVS24-2A>G, IVS27+1G>A, IVS27+1delGT, IVS27-3C>G, IVS28+1G>A, IVS32+1G>A, IVS33+1G>A (see http://cardiogenomics.med.harvard.edu/project-detail?project_id=230 for list and references). In total the variant has not been seen in 6800 laboratory controls, published controls and individuals from publicly available population datasets. The variant is not listed in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~6500 Caucasian and African American individuals (as of August 25th, 2014). There is also no variation at this codon listed in dbSNP or 1000 genomes (as of August 25th,2014). The variant was not observed in the following laboratory and published control samples: 200 laboratory controls (GeneDx), 100 published controls (Boone et al 1995). -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 16, 2024	Not observed at significant frequency in large population cohorts (gnomAD); Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 25525159, 30775854, 31006259, 20019025, 7493026, 12707239, 18957093, 22574137, 25078086, 26654849, 26358504, 25583989, 26920199, 27532257, 24510615, 25351510, 32341788, 31513939, 30847666, 31568572, 31333075, 33757590, 24704860, 33906374, 33673806, 37089884, 37937776, 37652022, 34400558, 35653365, 34076677, 9562578, 26914223) -
Pathogenic, criteria provided, single submitter	clinical testing	Blueprint Genetics	Nov 07, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jan 31, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Apr 19, 2019	- -

Hypertrophic cardiomyopathy 4

Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Oct 16, 2023	Criteria applied: PVS1,PS4,PM2_SUP -
Pathogenic, no assertion criteria provided	research	deCODE genetics, Amgen	Jul 21, 2023	The variant NM_000256.3:c.927-2A>G (chr11:47346372) in MYBPC3 was detected in 218 heterozygotes out of 58K WGS Icelanders (MAF= 0,188%). Following imputation in a set of 166K Icelanders (561 imputed heterozygotes) we observed an association with cardiomyopathy using 1974 cases and 365360 controls (OR= 48.62, P= 3.25e-170), heart failure using 20765 cases and 367806 controls (OR= 3.68, P= 1.27e-22), atrial fibrillation and flutter using 20168 cases and 351419 controls (OR= 2.73, P= 8.47e-12) and sudden cardiac death using 4784 cases and 358521 controls (OR= 1.93, P= 5.10e-03). This variant has been reported in ClinVar previously as pathogenic. Based on ACMG criteria (PVS1, PS4, PP5) this variant classifies as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 08, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Hypertrophic cardiomyopathy

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 01, 2019	The c.927-2A>G variant in MYBPC3 has been identified in several individuals with HCM, segregated with disease in >10 affected relatives, and was absent from 400 control chromosomes (Nimura 1998, Richard 2003, Ehlermann 2008), as well as in two large and broad populations screened NHLBI Exome sequencing project (http://evs.gs.washington.edu/EVS/). In addition, this variant affects the invariant (-1/-2) positions in the splice consensus sequence, and was confirmed to lead to aberrant splicing in lymphoblast cells from HCM patients with this variant (Nimura 1998). In summary, this variant meets our criteria for pathogenicity (http://pcpgm.partners.org/LMM) based on familial segregation analyses and the impact of the variant. -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Human Genetics, University of Leuven	Oct 31, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 17, 2024	This sequence change affects an acceptor splice site in intron 11 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). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. Disruption of this splice site has been observed in individuals with hypertrophic cardiomyopathy (PMID: 9562578, 22574137, 25078086, 27532257). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 42806). 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. -

Primary familial hypertrophic cardiomyopathy

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 28, 2022	Variant summary: MYBPC3 c.927-2A>G alters a conserved nucleotide 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. Several computational tools predict a significant impact on normal splicing: Two predict the variant abolishes the canonical 3' splice acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 5.1e-06 in 196860 control chromosomes. c.927-2A>G has been reported in the literature in multiple individuals affected with Hypertrophic Cardiomyopathy (example, Richard_2000, Niimura_1998). These data indicate that the variant is very likely to be associated with disease. Ten clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	research	Klaassen Lab, Charite University Medicine Berlin	Jul 03, 2019	- -

Cardiomyopathy

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Mar 07, 2023

- -

Cardiovascular phenotype

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 09, 2021

The c.927-2A>G intronic pathogenic mutation results from an A to G substitution two nucleotides upstream from coding exon 12 in the MYBPC3 gene. This alteration has been previously reported in association with hypertrophic cardiomyopathy (Niimura H et al. N. Engl. J. Med., 1998 Apr;338:1248-57 (reported as Int12ASA-2G); Richard P et al. Circulation, 2003 May;107:2227-32 (reported as IVS12–2:a7308g); Ehlermann P et al. BMC Med. Genet., 2008 Oct;9:95; Kuster DW et al. J. Mol. Cell. Cardiol., 2013 Dec;65:59-66; Walsh R et al. Genet. Med., 2017 Feb;19:192-203), and reported to segregate with disease in families (Niimura H et al. N. Engl. J. Med., 1998 Apr;338:1248-57; Ehlermann P et al. BMC Med. Genet., 2008 Oct;9:95; Adalsteinsdottir B et al. Open Heart, 2020 Apr;7:e001220). In addition, haplotype analysis has suggested this alteration to be a founder mutation in Iceland (Adalsteinsdottir B et al. Circulation, 2014 Sep;130:1158-67). 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

Pathogenic

0.21

BayesDel_noAF

Uncertain

0.060

CADD

Uncertain

DANN

Benign

0.96

Eigen

Pathogenic

0.90

Eigen_PC

Pathogenic

0.70

FATHMM_MKL

Benign

0.49

GERP RS

4.4

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

SpliceAI score (max)

0.61

Details are displayed if max score is > 0.2

DS_AL_spliceai

0.61

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.

rs397516082

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

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