11-47332565-C-T

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_000256.3(MYBPC3):​c.3627+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 0.000000688 in 1,453,302 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: 32)
Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

MYBPC3
NM_000256.3 splice_donor, intron

Scores

5
1
1
Splicing: ADA: 1.000
2

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:7

Conservation

PhyloP100: 7.56

Publications

3 publications found
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 Gene-Disease associations (from GenCC):
  • hypertrophic cardiomyopathy
    Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
  • hypertrophic cardiomyopathy 4
    Inheritance: AD, AR Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
  • left ventricular noncompaction 10
    Inheritance: AR, AD Classification: DEFINITIVE, MODERATE, LIMITED Submitted by: Ambry Genetics
  • familial isolated dilated cardiomyopathy
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
  • arrhythmogenic right ventricular cardiomyopathy
    Inheritance: AD Classification: LIMITED Submitted by: ClinGen
  • atrial fibrillation
    Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
  • dilated cardiomyopathy
    Inheritance: AD Classification: LIMITED Submitted by: ClinGen

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 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 11-47332565-C-T is Pathogenic according to our data. Variant chr11-47332565-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 42728.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
MYBPC3NM_000256.3 linkc.3627+1G>A splice_donor_variant, intron_variant Intron 32 of 34 ENST00000545968.6 NP_000247.2 Q14896-1A5YM48

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
MYBPC3ENST00000545968.6 linkc.3627+1G>A splice_donor_variant, intron_variant Intron 32 of 34 5 NM_000256.3 ENSP00000442795.1 Q14896-1
MYBPC3ENST00000399249.6 linkc.3627+1G>A splice_donor_variant, intron_variant Intron 31 of 33 5 ENSP00000382193.2 A8MXZ9

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
6.88e-7
AC:
1
AN:
1453302
Hom.:
0
Cov.:
35
AF XY:
0.00000139
AC XY:
1
AN XY:
721208
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33270
American (AMR)
AF:
0.00
AC:
0
AN:
44306
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
25930
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39482
South Asian (SAS)
AF:
0.00
AC:
0
AN:
85988
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53102
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5742
European-Non Finnish (NFE)
AF:
9.04e-7
AC:
1
AN:
1105638
Other (OTH)
AF:
0.00
AC:
0
AN:
59844
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.475
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
GnomAD4 genome
Cov.:
32
Alfa
AF:
0.00000536
Hom.:
0
EpiCase
AF:
0.0000545
EpiControl
AF:
0.00

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:7
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Primary familial hypertrophic cardiomyopathy Pathogenic:2
Feb 13, 2015
Blueprint Genetics
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Dec 19, 2022
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

Variant summary: MYBPC3 c.3627+1G>A 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. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 5' splicing donor site. The variant was absent in 246970 control chromosomes. c.3627+1G>A has been reported in the literature in multiple individuals affected with Hypertrophic Cardiomyopathy (examples: Ho_2018, Hathaway_2021, Walsh_2017, Tadros_2021) and was shown to segregate with disease in at least one large family (Nimura_1998). Six 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. -

Hypertrophic cardiomyopathy Pathogenic:2
Feb 01, 2019
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The c.3627+1G>A variant in MYBPC3 has been reported in over 8 individuals with hypertrophic cardiomyopathy (HCM) and segregated with disease in over 10 affected individuals in 2 families (Niimura 1998, Maron 2001, Ho 2009, Lopes 2015, Torrado 2017, LMM data). It was absent from large population studies. This variant occurs within the canonical splice site (+/- 1,2) and is predicted to cause altered splicing leading to an abnormal or absent protein. Loss of function of the MYBPC3 gene is an established disease mechanism in autosomal dominant HCM. In vitro functional studies support an impact on protein function (Torrado 2017). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant HCM. ACMG/AMP criteria applied: PVS1, PP1_Strong, PM2, PS4_Moderate. -

Feb 02, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This sequence change affects a donor splice site in intron 32 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 (HCM) (PMID: 9562578, 20031602, 25351510, 27532257). It has also been observed to segregate with disease in related individuals. This variant is also known as Int33DSG+1A. ClinVar contains an entry for this variant (Variation ID: 42728). 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
Apr 19, 2021
Color Diagnostics, LLC DBA Color Health
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This variant causes a G to A nucleotide substitution at the +1 position of intron 32 of the MYBPC3 gene. This variant is also known as Int33DSG+1A in the literature. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. Although this prediction has not been confirmed in published RNA studies, this variant is expected to result in an absent or disrupted protein product. This variant has been reported in many individuals affected with hypertrophic cardiomyopathy (PMID: 9562578, 9562578, 20031602, 25351510, 27532257). It has been shown that this variant segregates with disease in one family (PMID: 9562578). 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. -

not provided Pathogenic:1
Jun 06, 2023
GeneDx
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

Canonical splice site variant 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: 11815426, 27532257, 19574547, 34542152, 25351510, 25525159, 9562578, 20031602, 11499718, 33673806, 34135346, 35653365, 34076677) -

Cardiovascular phenotype Pathogenic:1
May 22, 2021
Ambry Genetics
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The c.3627+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 32 of the MYBPC3 gene. This alteration (referred to as Int33DSG+1A) has been identified in individuals with hypertrophic cardiomyopathy (HCM), confirmed to co-segregate with disease, and reported to result in aberrant RNA splicing (Niimura H et al. N. Engl. J. Med., 1998 Apr;338:1248-57; Ho CY et al. Circ Cardiovasc Genet, 2009 Aug;2:314-21; Lopes LR et al. Heart, 2015 Feb;101:294-301). 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
0.46
D
BayesDel_noAF
Pathogenic
0.43
CADD
Pathogenic
33
DANN
Uncertain
0.99
Eigen
Pathogenic
1.2
Eigen_PC
Pathogenic
1.0
FATHMM_MKL
Pathogenic
0.99
D
PhyloP100
7.6
GERP RS
5.3
Mutation Taster
=0/100
disease causing (ClinVar)

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_DL_spliceai
1.0
Position offset: 1

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

Publications

Other links and lift over

dbSNP: rs397516031; hg19: chr11-47354116; API