rs397516072
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000256.3(MYBPC3):c.772+1G>A variant causes a splice donor, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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: 30)
Consequence
MYBPC3
NM_000256.3 splice_donor, intron
NM_000256.3 splice_donor, intron
Scores
4
2
1
Splicing: ADA: 1.000
2
Clinical Significance
Conservation
PhyloP100: 7.86
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, No cryptic splice site detected. Exon removal results in frameshift change.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 11-47348423-C-T is Pathogenic according to our data. Variant chr11-47348423-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 42790.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-47348423-C-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
MYBPC3 | NM_000256.3 | c.772+1G>A | splice_donor_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.772+1G>A | splice_donor_variant, intron_variant | 5 | NM_000256.3 | ENSP00000442795.1 | ||||
MYBPC3 | ENST00000399249.6 | c.772+1G>A | splice_donor_variant, intron_variant | 5 | ENSP00000382193.2 | |||||
MYBPC3 | ENST00000544791.1 | n.772+1G>A | splice_donor_variant, intron_variant | 5 | ENSP00000444259.1 |
Frequencies
GnomAD3 genomes Cov.: 30
GnomAD3 genomes
Cov.:
30
GnomAD4 exome Cov.: 30
GnomAD4 exome
Cov.:
30
GnomAD4 genome Cov.: 30
GnomAD4 genome
Cov.:
30
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:7
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Nov 11, 2019 | The MYBPC3 c.772+1G>A variant (rs397516072), also published as IVS7+1G>A, is reported in the literature in multiple individuals affected with hypertrophic cardiomyopathy (Erdmann 2001, Walsh 2017). In one family, this variant was observed to segregate with disease in all affected members (Erdmann 2001). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. This variant abolishes the canonical splice donor site of intron 6, which is likely to disrupt gene function. Indeed, RNA analyses of individuals with this variant exhibit skipping of exon 6 or exons 6 and 7 (Erdmann 2001). Based on available information, this variant is considered to be pathogenic. References: Erdmann J et al. Spectrum of clinical phenotypes and gene variants in cardiac myosin-binding protein C mutation carriers with hypertrophic cardiomyopathy. J Am Coll Cardiol. 2001 Aug;38(2):322-30. Walsh R et al. Reassessment of Mendelian gene pathogenicity using 7,855 cardiomyopathy cases and 60,706 reference samples. Genet Med. 2017 Feb;19(2):192-203. - |
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Oct 09, 2019 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Apr 30, 2024 | Not observed at significant frequency in large population cohorts (gnomAD); Published RNA studies using patient lymphocytes show that this variant causes abnormal splicing, resulting in aberrant transcripts showing either the skipping of exon 6 or exons 6 and 7, which leads to frameshift events (PMID: 11499719); Published functional studies using a zebrafish model show that this variant causes impaired cardiac function and recapitulates features of a human HCM phenotype (PMID: 31943169); 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; Also denoted as IVS7+1G>A due to the use of alternate nomenclature; This variant is associated with the following publications: (PMID: 25611685, 27532257, 29398688, 11499719, 31943169) - |
Hypertrophic cardiomyopathy Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jun 10, 2011 | The 772+1G>A variant has been identified in four HCM probands (2 cases in Erdman 2001 - reported as IVS7+1G>A and 2 cases in our laboratory). One of these proba nds had a family history of HCM and the variant segregated with disease in three additional affected family members. This variant alters the highly conserved -1 splicing position, and has been shown to result in the skipping of exon 7 or ex ons 7 and 8, both of which cause a frame shift and a premature termination signa l (Erdmann 2001). In summary, this data meets our criteria to classify this vari ant as pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Nov 01, 2023 | This sequence change affects a donor splice site in intron 6 of the MYBPC3 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product. 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 (PMID: 11499719). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 42790). Studies have shown that disruption of this splice site results in skipping of exon 6 and exons 6 and 7 and introduces a premature termination codon (PMID: 11499719). The resulting mRNA is expected to undergo nonsense-mediated decay. 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 03, 2022 | - - |
Cardiovascular phenotype Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 27, 2022 | The c.772+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 6 of the MYBPC3 gene. This alteration (also referred to as IVS7+1G>A) has been reported in subjects with hypertrophic cardiomyopathy (HCM) and was shown to segregate with disease in one family (Erdmann J et al. J. Am. Coll. Cardiol., 2001 Aug;38:322-30; Alfares AA et al. Genet. Med., 2015 Nov;17:880-8; Walsh R et al. Genet. Med., 2017 02;19:192-203). This alteration has also been reported to impact mRNA splicing (Erdmann J et al. J. Am. Coll. Cardiol., 2001 Aug;38:322-30). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
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_DL_spliceai
Position offset: 1
Find out detailed SpliceAI scores and Pangolin per-transcript scores at