11-47333556-C-T

Position:

chr11-47333556-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_000256.3(MYBPC3):c.3190+1G>A variant causes a splice donor, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000313 in 1,599,896 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: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000028 ( 0 hom. )

Consequence

MYBPC3
NM_000256.3 splice_donor, intron

Scores

Splicing: ADA: 1.000

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:8O:1

Conservation

PhyloP100: 7.52

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:

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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, No cryptic splice site detected. Exon removal results in frameshift change.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 11-47333556-C-T is Pathogenic according to our data. Variant chr11-47333556-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 177837.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-47333556-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYBPC3	NM_000256.3 linkuse as main transcript	c.3190+1G>A		splice_donor_variant, intron_variant		ENST00000545968.6	NP_000247.2	Q14896-1A5YM48

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYBPC3	ENST00000545968.6 linkuse as main transcript	c.3190+1G>A		splice_donor_variant, intron_variant		5	NM_000256.3	ENSP00000442795.1		Q14896-1
MYBPC3	ENST00000399249.6 linkuse as main transcript	c.3190+1G>A		splice_donor_variant, intron_variant		5		ENSP00000382193.2		A8MXZ9

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152256

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000418

AC:

AN:

239082

Hom.:

AF XY:

0.00

AC XY:

AN XY:

130454

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.0000997

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000276

AC:

AN:

1447640

Hom.:

Cov.:

AF XY:

0.00000278

AC XY:

AN XY:

720582

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.000153

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152256

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74388

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hypertrophic cardiomyopathy 4

Pathogenic:2Other:1

not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	Feb 27, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	May 21, 2020	Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. (N) 0108 - This gene is known to be associated with both recessive and dominant disease. (N) 0211 - Canonical splice site variant without proven consequence on splicing (intron 29, no functional evidence available). (P) 0251 - Variant is heterozygous. (N) 0302 - Variant is present in gnomAD <0.001 (1 heterozygote, 0 homozygotes). (P) 0505 - Abnormal splicing is predicted by in silico tools and affected nucleotide is highly conserved. (P) 0703 - Comparable variants have moderate previous evidence for pathogenicity. Another variant in the same splice junction (c.3190+2T>G) has also been reported in patient's with hypertrophic cardiomyopathy (ClinVar, PMID: 24111713). (P) 0802 - Moderate previous evidence of pathogenicity in unrelated individuals. The variant has been previously reported as pathogenic in patients with dilated cardiomyopathy and hypertrophic cardiomyopathy (ClinVar, PMID: 20215591, 25132132, 25611685). (P) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign -

Hypertrophic cardiomyopathy

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 19, 2018	The c.3190+1G>A variant in MYBPC3 has been identified in at least 5 individuals with HCM (Wang 2015, LMM data) and in 1 individual with DCM (Hershberger 2010). This variant has also been identified in 1/9828 of Ashkenazi Jewish chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; db SNP rs111683277). This variant has also been reported in ClinVar (Variation ID: 177837). This variant occurs in the invariant region (+/- 1,2) of the splice con sensus sequence and is predicted to cause altered splicing leading to an abnorma l or absent protein. Splice site and other MYBPC3 variants resulting in a hetero zygous loss of function are strongly associated with HCM. In summary, this varia nt meets criteria to be classified as pathogenic for hypertrophic cardiomyopathy in an autosomal dominant manner based upon predicted impact to the protein and presence in affected individuals. ACMG/AMP Criteria applied: PVS1; PM2; PS4_Mode rate. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 05, 2023	This sequence change affects a donor splice site in intron 29 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 (rs111683277, gnomAD 0.01%). Disruption of this splice site has been observed in individuals with hypertrophic cardiomyopathy, dilated cardiomyopathy and dilated cardiomyopathy (PMID: 20215591, 25132132, 25611685, 27532257; Invitae). This variant is also known as splice site (29+1). ClinVar contains an entry for this variant (Variation ID: 177837). 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. -

Cardiomyopathy

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Oct 18, 2021

- -

Hypertrophic cardiomyopathy 4;C3715165:Left ventricular noncompaction 10

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Sep 14, 2021

- -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jun 01, 2022

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; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25525159, 25611685, 20215591, 27532257, 33673806, 34912951, 25132132) -

Cardiovascular phenotype

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 18, 2021

The c.3190+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 29 of the MYBPC3 gene. This alteration has been previously reported in hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM) cohorts (Hershberger RE et al. Circ Cardiovasc Genet. 2010;3:155-61 (reported as splice site 29+1); Wang J et al. Eur J Heart Fail. 2014;16:950-7; Alfares AA et al. Genet Med. 2015;17(11):880-8; Walsh R et al. Genet. Med., 2017 Feb;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 pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.36

BayesDel_noAF

Pathogenic

0.28

CADD

Pathogenic

DANN

Uncertain

0.99

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.83

FATHMM_MKL

Pathogenic

1.0

GERP RS

5.2

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.94

SpliceAI score (max)

0.99

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.99

Position offset: 1

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