11-47347854-C-A
Position:
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 10P and 1B. PM2PP5_Very_StrongBP4
The NM_000256.3(MYBPC3):c.821+3G>T variant causes a splice donor region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000708 in 1,412,096 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 7.1e-7 ( 0 hom. )
Consequence
MYBPC3
NM_000256.3 splice_donor_region, intron
NM_000256.3 splice_donor_region, intron
Scores
2
Splicing: ADA: 0.9341
2
Clinical Significance
Conservation
PhyloP100: 0.214
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]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 9 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 11-47347854-C-A is Pathogenic according to our data. Variant chr11-47347854-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 228869.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-47347854-C-A is described in Lovd as [Likely_pathogenic].
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.44). . Strength limited to SUPPORTING due to the PP5.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| MYBPC3 | NM_000256.3 | c.821+3G>T | splice_donor_region_variant, intron_variant | ENST00000545968.6 | NP_000247.2 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| MYBPC3 | ENST00000545968.6 | c.821+3G>T | splice_donor_region_variant, intron_variant | 5 | NM_000256.3 | ENSP00000442795 | P4 | |||
| MYBPC3 | ENST00000399249.6 | c.821+3G>T | splice_donor_region_variant, intron_variant | 5 | ENSP00000382193 | A2 | ||||
| MYBPC3 | ENST00000544791.1 | c.821+3G>T | splice_donor_region_variant, intron_variant, NMD_transcript_variant | 5 | ENSP00000444259 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
32
GnomAD4 exome AF: 7.08e-7 AC: 1AN: 1412096Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 697762
GnomAD4 exome
AF:
AC:
1
AN:
1412096
Hom.:
Cov.:
33
AF XY:
AC XY:
0
AN XY:
697762
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:7Uncertain:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Hypertrophic cardiomyopathy Pathogenic:3Uncertain:1
| Likely pathogenic, criteria provided, single submitter | research | Agnes Ginges Centre for Molecular Cardiology, Centenary Institute | Aug 22, 2019 | MYBPC3 c.821+3G>T variant has been reported in one HCM case, this proband carried another MYBPC3 variant however, only the c.821+3G>T variant segregated to another affected family member (Kassem HSh, et al., 2013). The variant is absent from the Genome Aggregation Database (http://gnomad.broadinstitute.org/). In silico tools MaxEntScan and AdaBoost predict that this variant is likely to cause aberrant splicing. We identified this heterozygous variant in a Lebanese child born into a consanguineous family who was diagnosed with severe HCM. Amplification of RNA extracted from septal myectomy tissue and blood showed skipping of exon 7 in MYBPC3 (Singer et al., 2019). Loss of exon 7 is predicted to result in a shift in the reading frame and a subsequent premature stop codon . Based on the adapted ACMG criteria (Kelly MA, et al., 2018) this variant is very rare in the general population (PM2), in silico tools predict aberrant splicing to occur and this was confirmed in RNA studies which showed exon 7 skipping (PS3), and the variant has been reported in a total of 2 unrelated HCM probands (PS4_supporting), therefore we classify MYBPC3 c.821+3G>T as 'likely pathogenic'. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Oct 14, 2020 | For these reasons, this variant has been classified as Pathogenic. Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant is associated with exon skipping, which introduces a frameshift (PMID: 30645170). The resulting mRNA is expected to undergo nonsense-mediated decay. This variant has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 23233322, 30645170, 31513939). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 228869). This variant is not present in population databases (ExAC no frequency). This sequence change falls in intron 7 of the MYBPC3 gene. It does not directly change the encoded amino acid sequence of the MYBPC3 protein. RNA analysis indicates that this variant induces altered splicing and likely results in a truncated protein product. - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Apr 05, 2022 | The p.821+3G>T variant in MYBPC3 has been reported in 4 individuals with hypertrophic cardiomyopathy (HCM) and segregated with disease in 3 affected individuals from 3 families (Kassem 2013 PMID: 23233322, Singer 2019 PMID: 30645170, Robyns 2020 PMID: 31513939, LMM data). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID 228869) and was absent from large population studies. This variant is located in the 5' splice region. Computational tools predict a splicing impact, which is corroborated by in vitro functional studies on patient RNA from both blood and cardiac myocardium that show that this variant results in the skipping of exon 7 (Singer 2019 PMID: 30645170). Loss of exon 7 is predicted to result in a frameshift and a subsequent premature termination codon. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant HCM. ACMG/AMP Criteria applied: PS4_Supporting, PM2_Supporting, PS3_Moderate, PP1, PP3. - |
| Uncertain significance, flagged submission | clinical testing | Center for Human Genetics, University of Leuven | Oct 31, 2018 | - - |
Cardiomyopathy Pathogenic:1
| Likely pathogenic, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Nov 09, 2017 | - - |
not provided Pathogenic:1
| Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jul 02, 2024 | Published functional studies suggest skipping of exon 7 (PMID: 30645170); Not observed in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 31513939, 23233322, 30645170, 36243179, 36252119, 36264615) - |
Hypertrophic cardiomyopathy 4 Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Jul 16, 2023 | Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with dilated cardiomyopathy 1MM (MIM#615396), hypertrophic cardiomyopathy 4 (MIM#115197) and left ventricular noncompaction 10 (MIM#615396) (OMIM). (I) 0108 - This gene is associated with both recessive and dominant disease. Heterozygous variants are frequently reported in adult onset conditions, however recessive inheritance results in a more severe early onset phenotype (OMIM). (I) 0210 - Splice site variant proven to affect splicing of the transcript with a known effect on protein sequence. Analysis of RNA from individuals heterozygous for this variant have demonstrated the out-of-frame skipping of exon 7, resulting in a premature termination codon (p.(Glu258Glyfs*26)) which is predicted to undergo NMD (PMID: 30645170). (SP) 0115 - Variants in this gene are known to have variable expressivity (PMID: 32841044). (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0311 - An alternative nucleotide change at the same canonical splice site, is present in gnomAD (v3) (1 heterozygote, 0 homozygotes). (I) 0701 - Other null variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. Other NMD-predicted variants have been classfied as likely pathogenic and pathogenic by multiple clinical diagnostic laboratories (DECIPHER). It should also be noted that alternate splice site variants affecting the same nucleotide position (c.821+3G>A, c.821+3G>C) have been reported as VUS favouring pathogenicity, and observed in an individual with HCM (ClinVar, PMID: 26656175). (SP) 0808 - Previous reports of pathogenicity for this variant are conflicting. This variant has been reported in at least seven unrelated individuals (including two families) with HCM and has been classified as either a VUS, likely pathogenic or pathogenic (ClinVar, LOVD, PMIDs: 23233322, 31513939, 30645170). (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign - |
Cardiovascular phenotype Pathogenic:1
| Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 25, 2021 | The c.821+3G>T intronic variant results from a G to T substitution 3 nucleotides after coding exon 7 in the MYBPC3 gene. This variant has been reported in multiple individuals with hypertrophic cardiomyopathy (HCM) and has been shown to segregate with disease in two affected relatives (Kassem HSh et al. J Cardiovasc Transl Res, 2013 Feb;6:65-80; Singer ES et al. Circ Genom Precis Med, 2019 01;12:e002368; Robyns T et al. Eur J Med Genet, 2020 Mar;63:103754; Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is not well conserved in available vertebrate species. However, in silico splice site analysis predicts that this alteration will weaken the native splice donor site, and RNA studies have demonstrated exon 7 skipping in heterozygous individuals (Singer ES et al. Circ Genom Precis Med, 2019 01;12:e002368). Based on the majority of available evidence to date, this variant is likely to be pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
dbscSNV1_RF
Benign
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DL_spliceai
Position offset: 3
Find out detailed SpliceAI scores and Pangolin per-transcript scores at