rs397516044

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 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

Scores

3
2
2
Splicing: ADA: 1.000
2

Clinical Significance

Likely pathogenic criteria provided, multiple submitters, no conflicts P:10

Conservation

PhyloP100: 1.20
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]

Genome browser will be placed here

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

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
MYBPC3NM_000256.3 linkuse as main transcriptc.3815-1G>A splice_acceptor_variant ENST00000545968.6 NP_000247.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
MYBPC3ENST00000545968.6 linkuse as main transcriptc.3815-1G>A splice_acceptor_variant 5 NM_000256.3 ENSP00000442795 P4Q14896-1
MYBPC3ENST00000399249.6 linkuse as main transcriptc.3815-1G>A splice_acceptor_variant 5 ENSP00000382193 A2

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD3 exomes
AF:
0.00000412
AC:
1
AN:
242650
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
131818
show subpopulations
Gnomad AFR exome
AF:
0.0000685
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:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000206
AC:
3
AN:
1458124
Hom.:
0
Cov.:
31
AF XY:
0.00000138
AC XY:
1
AN XY:
724984
show subpopulations
Gnomad4 AFR exome
AF:
0.0000898
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:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
33
Bravo
AF:
0.0000113

ClinVar

Significance: Likely pathogenic
Submissions summary: Pathogenic:10
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Primary familial hypertrophic cardiomyopathy Pathogenic:3
Likely pathogenic, criteria provided, single submitterclinical testingMolecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart InstituteDec 23, 2016- -
Likely pathogenic, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpJul 23, 2024Variant 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 submitterclinical testingBlueprint GeneticsDec 07, 2015- -
Hypertrophic cardiomyopathy Pathogenic:3
Likely pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpDec 13, 2023This 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; Invitae). 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. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -
Likely pathogenic, criteria provided, single submitterclinical testingAll of Us Research Program, National Institutes of HealthJul 19, 2023This 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. -
Likely pathogenic, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineSep 30, 2011The 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. -
not provided Pathogenic:2
Pathogenic, no assertion criteria providedresearchGharavi Laboratory, Columbia UniversitySep 16, 2018- -
Likely pathogenic, criteria provided, single submitterclinical testingGeneDxOct 02, 2024Identified 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 submitterclinical testingColor Diagnostics, LLC DBA Color HealthJun 01, 2023This 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. -
Cardiovascular phenotype Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingAmbry GeneticsDec 01, 2021The 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: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Uncertain
0.16
D
BayesDel_noAF
Pathogenic
0.18
CADD
Pathogenic
33
DANN
Uncertain
0.99
Eigen
Pathogenic
0.96
Eigen_PC
Pathogenic
0.80
FATHMM_MKL
Benign
0.64
D
MutationTaster
Benign
1.0
D;D;D
GERP RS
4.4

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
1.0
dbscSNV1_RF
Pathogenic
0.93
SpliceAI score (max)
0.89
Details are displayed if max score is > 0.2
DS_AG_spliceai
0.22
Position offset: -9
DS_AL_spliceai
0.89
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.

Other links and lift over

dbSNP: rs397516044; hg19: chr11-47353433; API