chr11-47337502-G-GA
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Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong
The NM_000256.3(MYBPC3):c.2490dupT(p.His831SerfsTer2) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000372 in 1,613,888 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 31)
Exomes 𝑓: 0.0000034 ( 0 hom. )
Consequence
MYBPC3
NM_000256.3 frameshift
NM_000256.3 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 0.0200
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 16 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PP5
Variant 11-47337502-G-GA is Pathogenic according to our data. Variant chr11-47337502-G-GA is described in ClinVar as [Likely_pathogenic]. Clinvar id is 42625.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| MYBPC3 | ENST00000545968.6 | c.2490dupT | p.His831SerfsTer2 | frameshift_variant | Exon 25 of 35 | 5 | NM_000256.3 | ENSP00000442795.1 | ||
| MYBPC3 | ENST00000399249.6 | c.2490dupT | p.His831SerfsTer2 | frameshift_variant | Exon 24 of 34 | 5 | ENSP00000382193.2 | |||
| MYBPC3 | ENST00000544791.1 | n.2422dupT | non_coding_transcript_exon_variant | Exon 25 of 27 | 5 | ENSP00000444259.1 |
Frequencies
GnomAD3 genomes 0.00000657 AC: 1AN: 152210Hom.: 0 Cov.: 31
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GnomAD3 exomes AF: 0.0000120 AC: 3AN: 249168Hom.: 0 AF XY: 0.00000740 AC XY: 1AN XY: 135156
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GnomAD4 exome AF: 0.00000342 AC: 5AN: 1461678Hom.: 0 Cov.: 33 AF XY: 0.00000275 AC XY: 2AN XY: 727128
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GnomAD4 genome 0.00000657 AC: 1AN: 152210Hom.: 0 Cov.: 31 AF XY: 0.0000134 AC XY: 1AN XY: 74368
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:9
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:4
| Pathogenic, criteria provided, single submitter | clinical testing | Blueprint Genetics | Nov 20, 2018 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Aug 18, 2023 | PM2, PS4_moderate, PVS1 - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Nov 11, 2024 | Not observed at significant frequency in large population cohorts (gnomAD); Also known as c.2490_2491insT and S830 fs/1; Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 21839045, 24510615, 29237689, 27532257, 33673806, 31980526, 33190526, 37652022, 35653365, 34542152, 15519027) - |
| Likely pathogenic, no assertion criteria provided | provider interpretation | Stanford Center for Inherited Cardiovascular Disease, Stanford University | May 27, 2016 | c.2490dupT (p.His831Serfs*2) in the MYBPC3 gene Given the fact that this is a loss of function variant in a gene where loss of function is a well-established mechanism of disease and a moderate amount of case data, we consider this variant to be likely pathogenic and we do feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). We have seen the variant in an individual with HCM. The variant has been seen in at least 3 unrelated cases of HCM (not including this patient's family). This is moderate case data. It has been reported in 2 cases in the literature. Van Driest et al., 2004 reported the variant using alternative nomenclature (S830 fs/1) in a patient with HCM. Maron et al., 2012 reported the variant in a series of compound heterozygote patients. The patient had HCM and this variant as well as a MYH7 Arg1832Cys variant. This frameshift variant is expected to result in a truncated or absent protein product because of nonsense mediated mRNA decay. Loss of function is an established mechanism of disease in the MYBPC3 gene. The variant was reported online in 3 of 60,340 individuals in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/), which currently includes variant calls on ~64,000 individuals of European, African, Latino and Asian descent (as of 5/26/16). Specifically, the variant was observed in 3 of 33,340 non-Finnish European people. The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease. Note that other variants with strong evidence for pathogenicity have been seen at similar frequencies in datasets like this so this does not necessarily rule out pathogenicity (Pan et al 2012). - |
Hypertrophic cardiomyopathy Pathogenic:3
| Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Feb 04, 2015 | The p.His831fs variant in MYBPC3 has been observed in at least 4 individuals wit h HCM (Van Driest 2004, Kapplinger 2014, LMM unpublished data) and segregated wi th disease in 1 affected relative (LMM unpublished data). This variant has also been identified in 3/66680 of European chromosomes by the Exome Aggregation Cons ortium (ExAC, http://exac.broadinstitute.org; dbSNP rs397515966). Please note th at for diseases with clinical variability and reduced penetrance, pathogenic var iants may be present at a low frequency in the general population. This variant is predicted to cause a frameshift, which alters the protein?s amino acid sequen ce beginning at position 831 and leads to a premature termination codon 2 amino acids downstream. This alteration is then predicted to lead to a truncated or ab sent protein. Heterozygous loss of function of function of the MYBPC3 gene is an established disease mechanism in HCM. In summary, this variant meets our criter ia to be classified as pathogenic for HCM in an autosomal dominant manner (http: //www.partners.org/personalizedmedicine/LMM) based on the predicted impact of th e variant. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Clinical Genetics Laboratory, Skane University Hospital Lund | Dec 16, 2019 | ACMG criteria met: PVS1, PS4 - |
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 12, 2024 | This sequence change creates a premature translational stop signal (p.His831Serfs*2) in the MYBPC3 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MYBPC3 are known to be pathogenic (PMID: 19574547). This variant is present in population databases (rs397515966, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 15519027, 21839045). ClinVar contains an entry for this variant (Variation ID: 42625). For these reasons, this variant has been classified as Pathogenic. - |
Hypertrophic cardiomyopathy 4 Pathogenic:1
| Likely pathogenic, criteria provided, single submitter | clinical testing | Clinical Genetics Laboratory, Region Ostergotland | Apr 04, 2022 | PVS1, PS4, PP5 - |
Primary familial hypertrophic cardiomyopathy Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Oct 01, 2018 | Variant summary: MYBPC3 c.2490dupT (p.His831SerfsX2) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 1.2e-05 in 246844 control chromosomes. c.2490dupT has been reported in the literature in multiple individuals affected with Hypertrophic Cardiomyopathy (VanDriest 2004 Maron 2012, Kapplinger 2014, Walsh 2017). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic (3x) / likely pathogenic (1x). Based on the evidence outlined above, the variant was classified as pathogenic. - |
Computational scores
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SpliceAI score (max)
Details are displayed if max score is > 0.2
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