rs397516044
Variant names:
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000256.3(MYBPC3):c.3815-1G>A variant causes a splice acceptor, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000206 in 1,458,124 control chromosomes in the GnomAD database, with no homozygous occurrence. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: not found (cov: 33)
Exomes 𝑓: 0.0000021 ( 0 hom. )
Consequence
MYBPC3
NM_000256.3 splice_acceptor, intron
NM_000256.3 splice_acceptor, intron
Scores
3
2
2
Splicing: ADA: 1.000
2
Clinical Significance
Conservation
PhyloP100: 1.20
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]
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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, Cryptic splice site detected, with MaxEntScore 4.3, offset of 8, new splice context is: cctcttctgcaatgcctcAGtga. 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 11-47331882-C-T is Pathogenic according to our data. Variant chr11-47331882-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 42746.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-47331882-C-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| MYBPC3 | ENST00000545968.6 | c.3815-1G>A | splice_acceptor_variant, intron_variant | Intron 33 of 34 | 5 | NM_000256.3 | ENSP00000442795.1 | |||
| MYBPC3 | ENST00000399249.6 | c.3815-1G>A | splice_acceptor_variant, intron_variant | Intron 32 of 33 | 5 | ENSP00000382193.2 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
33
GnomAD3 exomes AF: 0.00000412 AC: 1AN: 242650Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 131818
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GnomAD4 exome AF: 0.00000206 AC: 3AN: 1458124Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1AN XY: 724984
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:11
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Hypertrophic cardiomyopathy Pathogenic:3
| Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Sep 30, 2011 | The 3815-1G>A variant has not been previously reported or been identified by our laboratory. This variant is predicted to cause abnormal splicing because the nu cleotide substitution occurs in the highly conserved splice consensus sequence. Pathogenic splice variants in MYBPC3 are common in patients with HCM, which sup ports a disease causing role. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 30, 2025 | This sequence change affects an acceptor splice site in intron 33 of the MYBPC3 gene. While this variant is not anticipated to result in nonsense mediated decay, it likely alters RNA splicing and results in a disrupted protein product. This variant is present in population databases (rs397516044, gnomAD 0.007%). Disruption of this splice site has been observed in individuals with clinical features of hypertrophic cardiomyopathy (PMID: 25611685, 27532257, 33673806, 37652022; internal data). ClinVar contains an entry for this variant (Variation ID: 42746). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). 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. - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | May 14, 2024 | This variant causes a G to A nucleotide substitution at the -1 position of intron 33 of the MYBPC3 gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. The mutant transcript is expected to escape nonsense-mediated decay and be expressed as a protein product containing altered C-terminal sequence. To our knowledge, protein functional studies have not been reported for this variant. This variant has been reported in at least fourteen individuals affected with hypertrophic cardiomyopathy including an affected family member (PMID: 25611685, 27532257, 33495596, 33495597, 33663232, 33673806; communication with external laboratories: ClinVar SCV000739990.4, SCV000208208.11). This variant has been identified in 1/242650 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. - |
Primary familial hypertrophic cardiomyopathy Pathogenic:3
| Likely pathogenic, criteria provided, single submitter | clinical testing | Blueprint Genetics | Dec 07, 2015 | - - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jul 23, 2024 | Variant summary: MYBPC3 c.3815-1G>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 3' acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant is located in intron 33, and the potentially skipped penultimate exon (exon 34) only encodes the last 3 amino acids of the protein, thus the protein level effect of this variant is unclear. The variant allele was found at a frequency of 4.1e-06 in 242650 control chromosomes (gnomAD). c.3815-1G>A has been reported in the literature in individuals affected with Hypertrophic Cardiomyopathy (e.g. Alfares_2015, Walsh_2017, Tadros_2021, Harper_2021, Hathaway_2021, Schafer_2021, McGurk_2023). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. ClinVar contains an entry for this variant (Variation ID: 42746). The following publications have been ascertained in the context of this evaluation (PMID: 25611685, 27532257, 33495596, 33495597, 33673806, 33663232, 37652022). Based on the evidence outlined above, the variant was classified as likely pathogenic. - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute | Dec 23, 2016 | - - |
not provided Pathogenic:2
| Pathogenic, no assertion criteria provided | research | Gharavi Laboratory, Columbia University | Sep 16, 2018 | - - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Oct 02, 2024 | Identified in multiple patients with cardiomyopathy referred for genetic testing at GeneDx and in the published literature (PMID: 25611685, 27532257, 33673806, 33663232, 37652022); Not observed at significant frequency in large population cohorts (gnomAD); Canonical splice site variant with an unclear effect on protein function; This variant is associated with the following publications: (PMID: 25611685, 27532257, 33673806, 33663232, 37652022) - |
Cardiomyopathy Pathogenic:1
| Likely pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jun 01, 2023 | This variant causes a G to A nucleotide substitution at the -1 position of intron 33 of the MYBPC3 gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. The mutant transcript is expected to escape nonsense-mediated decay and be expressed as a protein product containing altered C-terminal sequence. To our knowledge, protein functional studies have not been reported for this variant. This variant has been reported in at least fourteen individuals affected with hypertrophic cardiomyopathy including an affected family member (PMID: 25611685, 27532257, 33495596, 33495597, 33663232, 33673806; communication with external laboratories: ClinVar SCV000739990.4, SCV000208208.11). This variant has been identified in 1/242650 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. - |
Hypertrophic cardiomyopathy 4 Pathogenic:1
| Likely pathogenic, criteria provided, single submitter | clinical testing | Clinical Genomics Laboratory, Stanford Medicine | Sep 02, 2022 | The c.3815-1G>A variant in the MYBPC3 gene has been previously reported in 3 unrelated individuals with HCM (Alfares et al., 2015; Walsh et al., 2017; Hathaway et al., 2021). This variant has also been identified in 1/14604 African/African American chromosomes by the Genome Aggregation Database (http://gnomad.broadinstitute.org/). This variant is present in ClinVar (Variation ID: 42746). This variant alters the canonical acceptor splice site in intron 32, which is predicted to result in abnormal gene splicing. Heterozygous loss of function is an established mechanism of disease for the MYBPC3 gene.These data were assessed using the ACMG/AMP variant interpretation guidelines. In summary, there is sufficient evidence to classify the c.38151G>A variant as likely pathogenic for autosomal dominant hypertrophic cardiomyopathy based on the information above. [ACMG evidence codes used: PVS1_Strong; PS4_Supporting; PM2]_x000D_ - |
Cardiovascular phenotype Pathogenic:1
| Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 01, 2021 | The c.3815-1G>A intronic variant results from a G to A substitution one nucleotide upstream from coding exon 34 of the MYBPC3 gene. 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. This alteration occurs at the 3' terminus of the MYBPC3 gene, is not expected to trigger nonsense-mediated mRNAdecay, and results in a frameshift that is predicted to impact only the last 3 amino acids of the native protein, although it is also expected to elongate the translated protein. The exact functional effect of this alteration is unknown. This variant has been identified in patients with hypertrophic cardiomyopathy (HCM) (Alfares AA et al. Genet Med, 2015 Nov;17:880-8; Walsh R et al. Genet Med, 2017 02;19:192-203; Ambry internal data). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site. 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_addAF
Uncertain
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Benign
D
GERP RS
Splicing
Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_AG_spliceai
Position offset: -9
DS_AL_spliceai
Position offset: -1
Find out detailed SpliceAI scores and Pangolin per-transcript scores at