rs397515937
Variant summary
Our verdict is Pathogenic. Variant got 20 ACMG points: 20P and 0B. PVS1PP3_StrongPP5_Very_Strong
The NM_000256.3(MYBPC3):c.1928-2A>G variant causes a splice acceptor change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000137 in 1,460,836 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
Consequence
NM_000256.3 splice_acceptor
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 20 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MYBPC3 | NM_000256.3 | c.1928-2A>G | splice_acceptor_variant | ENST00000545968.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MYBPC3 | ENST00000545968.6 | c.1928-2A>G | splice_acceptor_variant | 5 | NM_000256.3 | P4 | |||
MYBPC3 | ENST00000399249.6 | c.1928-2A>G | splice_acceptor_variant | 5 | A2 | ||||
MYBPC3 | ENST00000544791.1 | c.1928-2A>G | splice_acceptor_variant, NMD_transcript_variant | 5 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD4 exome AF: 0.0000137 AC: 20AN: 1460836Hom.: 0 Cov.: 31 AF XY: 0.00000826 AC XY: 6AN XY: 726538
GnomAD4 genome ? Cov.: 33
ClinVar
Submissions by phenotype
Hypertrophic cardiomyopathy Pathogenic:6
Pathogenic, criteria provided, single submitter | clinical testing | Center for Human Genetics, University of Leuven | Oct 31, 2018 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Aug 14, 2019 | The c.1928-2A>G variant in MYBPC3 has been identified in >40 individuals with hypertrophic cardiomyopathy (HCM) and segregated with disease in >20 affected relatives across several families (Bonne 1995, Charron 1998, Erdmann 2001, Richard 2003, Fokstuen 2008, Millat 2010, Teirlinck 2012, Valente 2013, Kapplinger 2014, LMM data). It has also been reported by other clinical laboratories in ClinVar (Variation ID:42585) and was absent from large population studies. This variant occurs in the invariant region (+/- 1,2) of the splice consensus sequence and has been shown to lead to aberrant splicing and subsequently a premature stop codon at position 661 (Bonne 1995, Flavigny 1999, Erdmann 2001). Please note that alternate nomenclature was used in some studies (Charron 1998: SAS int20; Richard 2003: IVS21-2A>G; Erdmann 2001: IVS20-2A>G). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant HCM. ACMG/AMP criteria applied: PS4, PP1_Strong, PM2, PS3. - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 26, 2024 | This sequence change affects an acceptor splice site in intron 20 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 (PMID: 7493026, 11499719, 12707239, 18409188, 20439259, 20624503, 23140321, 23690394, 24510615). ClinVar contains an entry for this variant (Variation ID: 42585). Studies have shown that disruption of this splice site alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 10610770, 11499719, 25031304). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Molecular Genetics, Royal Melbourne Hospital | Aug 01, 2023 | This sequence change in MYBPC3 occurs within the canonical splice acceptor site of intron 20. It is predicted to cause cryptic acceptor activation resulting in an 11bp deletion in exon 21 leading to premature termination codon and nonsense-mediated decay in a gene in which loss-of-function is an established disease mechanism. This prediction is confirmed by RT-PCR in patient cells (PMID: 7493026, 25031304). An assay also detected intron 20 inclusion predicting a premature termination codon introduced in intron 20 resulting in the disruption in the production of the MYBPC3 protein (PMID: 25031304). This variant is absent from the population database gnomAD v2.1 and v3.1. This variant has been reported in multiple unrelated individuals with hypertrophic cardiomyopathy (PMID: 23140321, 7493026, 12707239, 24510615, 9503187, 11499719, 20439259). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.6.1, this variant is classified as PATHOGENIC. Following criteria are met: PVS1, PS4, PM2_Supporting. - |
Pathogenic, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Jan 08, 2024 | The c.1928-2A>G variant of the MYBPC3 gene is predicted to disrupt the acceptor splice site in intron 20, resulting in abnormal RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547). Loss-of-function variants in MYBPC3 are known to be pathogenic (PMID: 19574547). This variant was first reported in two large French kindreds with hypertrophic cardiomyopathy (HCM) (PMID: 7493026) and has since then been reported in multiple unrelated individuals and families with HCM (PMID: 11499719, 12707239, 18409188, 20439259, 20624503, 23140321, 23690394, 24510615). This variant has been shown to lead to abnormal mRNA splicing and result in loss of protein expression (PMID: 10610770, 11499719, 25031304). This variant is absent in the general population (gnomAD). Based on these evidence, the c.1928-2A>G variant in MYBPC3 is classified as pathogenic. - |
Pathogenic, no assertion criteria provided | research | Agnes Ginges Centre for Molecular Cardiology, Centenary Institute | Dec 11, 2019 | The MYBPC3 c.1928-2A>G variant has been identified in numerous HCM probands and has been shown to segregate with disease across several reported families (see references). This variant occurs at the canonical acceptor splice site of intron 20 and leads to aberrant splicing and subsequently a premature stop codon (Bonne G., et al 1995; Flavigny J., et al 1999; Erdmann J., et al 2001; Helms AS, et al., 2010). This variant is absent in the Genome Aggregation Database (http://gnomad.broadinstitute.org/). We have identified this variant in 9 HCM probands. Based on the adapted ACMG guidelines (Kelly MA, et al., 2018) this variant results in loss of function of MYBPC3 (PVS1), has been reported in more than 15 HCM probands (PS4), segregated in multiple families (PP1_Strong) and is rare in the general population (PM2), therefore we classify MYBPC3 c.1928A>G as 'Pathogenic'. - |
not provided Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen | Oct 23, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Nov 01, 2022 | MYBPC3: PVS1, PM2 - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Dec 06, 2021 | Not observed at significant frequency in large population cohorts (gnomAD); Canonical splice site variant in a gene for which loss-of-function is a known mechanism of disease; mRNA functional studies have demonstrated this variant leads to aberrant gene splicing and the introduction of a premature stop codon (Bonne et al., 1995; Erdmann et al., 2001; Helms et al., 2014); Multiple other splice site variants in the MYBPC3 gene have been reported in the Human Gene Mutation Database in association with HCM (HGMD); Reported in ClinVar as pathogenic (ClinVar Variant ID# 42585; ClinVar); This variant is associated with the following publications: (PMID: 25031304, 20439259, 10610770, 28597742, 20624503, 24865491, 12707239, 9503187, 18409188, 23140321, 23348723, 25525159, 25611685, 23690394, 26743238, 26914223, 27532257, 28822653, 28369730, 24510615, 28790153, 25351510, 30128729, 31006259, 30550750, 31447099, 27688314, 31513939, 11499719, 7493026, 31737537, 33954932) - |
Hypertrophic cardiomyopathy 4 Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Center of Genomic medicine, Geneva, University Hospital of Geneva | Jul 06, 2018 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Center for Medical Genetics Ghent, University of Ghent | Feb 09, 2016 | This variant has not been identified in large population databases (Gnomad, 1000 Genomes, Go NL, Exome Variant Server) and is predicted to have an impact on protein function according to multiple prediction programs. In addition, the variant has been reported previously in individuals with cardiomyopathy. The c.1928-2 A>G variant affects the canonical splice acceptor site of intron 20 and leads to aberrant gene splicing and the introduction of a premature stop codon (PMID: 11499719; PMID: 7493026; PMID: 25031304). - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Dec 01, 1995 | - - |
Primary familial hypertrophic cardiomyopathy Pathogenic:3
Pathogenic, no assertion criteria provided | clinical testing | Blueprint Genetics | Oct 07, 2014 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jan 23, 2024 | Variant summary: MYBPC3 c.1928-2A>G 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. Publications report experimental evidence that this variant affects mRNA splicing (Erdmann_2001, Bonne_1995). The variant was absent in 248758 control chromosomes. c.1928-2A>G has been reported in the literature in numerous individuals and families affected with Hypertrophic Cardiomyopathy (ie. Erdmann_2001, Bonne_1995, Fokstuen_MYH7_2008. ClinVar contains an entry for this variant (Variation ID: 42585). Based on the evidence outlined above, the variant was classified as pathogenic. - |
Cardiomyopathy Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | May 18, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Mar 08, 2023 | This variant causes an A to G nucleotide substitution at the -2 position of intron 20 of the MYBPC3 gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. RNA studies have confirmed that this variant causes aberrant splicing and is expected to result in an absent or disrupted protein product (PMID: 11499719, 25031304). This variant has been reported in over 30 individuals affected with hypertrophic cardiomyopathy (PMID: 7493026, 11499719, 18409188, 20439259, 20624503, 23140321, 23690394, 24510615, 28615295). 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. - |
Hypertrophic cardiomyopathy 4;C3715165:Left ventricular noncompaction 10 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | May 18, 2017 | - - |
Cardiovascular phenotype Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | May 25, 2023 | The c.1928-2A>G intronic variant results from an A to G substitution two nucleotides before coding exon 21 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 variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This alteration was first reported in two large French kindreds with hypertrophic cardiomyopathy (HCM) (Bonne, 1995), and has since been reported in multiple unrelated individuals and families with HCM (Charron, 1998 (reported as SAS int20); Richard, 2003 (reported as IVS21-2A>G); Teirlinck, 2012 (reported as IVS202A>G); Kapplinger, 2014). This alteration has been shown to lead to abnormal splicing resulting in aberrant protein product (Bonne, 1995; Erdmann, 2001). In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site and will result in the creation or strengthening of a novel splice acceptor site. Based on the available evidence, this alteration is classified as pathogenic. - |
MYBPC3-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Aug 14, 2018 | The MYBPC3 c.1928-2A>G variant occurs in a canonical splice site (acceptor) and is therefore predicted to disrupt or distort the normal gene product. The c.1928-2A>G variant has not been observed in individuals with either autosomal dominant dilated cardiomyopathy or left ventricular noncompaction cardiomyopathy. Across a selection of the available literature, the c.1928-2A>G variant has been identified in a heterozygous state in 28 families in which it was found in 82 individuals affected with hypertrophic cardiomyopathy, of whom up to 35 individuals are related, in five individuals with an unknown diagnosis or discrete signs of disease, and in six healthy carriers (Bonne et al. 1995; Charron et al. 1998; Erdmann et al. 2001; Richard et al. 2003; Teirlinck et al. 2012). The c.1928-2A>G variant was shown to segregate with disease in two four-generation French families and in a further 13 families of European origin (Bonne et al. 1995; Richard et al. 2003). One of the studies calculated disease penetrance to be 69% and described the variant as being associated with a mild ventricular hypertrophy (Charron et al. 1998). The c.1928-2A>G variant was absent from 600 control chromosomes and is not found in the 1000 Genomes Project, the Exome Sequencing Project, Exome Aggregation Consortium or the Genome Aggregation Database in a region of good sequence coverage so the variant is presumed to be rare. Analysis of MYBPC3 mRNA from patient lymphoblastoid cell lines showed that the c.1928-2A>G variant results in aberrant splicing, causing the skipping of exon 21 and a frameshift with the introduction of a premature stop codon after amino acid residue 661 (Bonne et al. 1995). Expression of the c.1928-2A>G variant in COS-7 cells revealed accumulation to a level similar to wild type, while in fetal rat cardiomyocytes, the variant accumulated to a level that was approximately two-thirds of wild type. Eleven percent of fetal rat cardiomyocyte cells expressing the variant localized correctly in double stripes in the A-band of the sarcomere, but in a more diffuse pattern compared to wild type (Flavigny et al. 1999). Based on the collective evidence and due to the potential impact of splice acceptor variants, the c.1928-2A>G variant is classified as pathogenic for MYBPC3-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at