rs730880336
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Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000256.3(MYBPC3):c.1042_1043insCGGCA(p.Met348ThrfsTer4) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 32)
Consequence
MYBPC3
NM_000256.3 frameshift
NM_000256.3 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 4.69
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
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 11-47346254-A-ATGCCG is Pathogenic according to our data. Variant chr11-47346254-A-ATGCCG is described in ClinVar as [Pathogenic]. Clinvar id is 177698.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MYBPC3 | NM_000256.3 | c.1042_1043insCGGCA | p.Met348ThrfsTer4 | frameshift_variant | 12/35 | ENST00000545968.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MYBPC3 | ENST00000545968.6 | c.1042_1043insCGGCA | p.Met348ThrfsTer4 | frameshift_variant | 12/35 | 5 | NM_000256.3 | P4 | |
MYBPC3 | ENST00000399249.6 | c.1042_1043insCGGCA | p.Met348ThrfsTer4 | frameshift_variant | 11/34 | 5 | A2 | ||
MYBPC3 | ENST00000544791.1 | c.1042_1043insCGGCA | p.Met348ThrfsTer4 | frameshift_variant, NMD_transcript_variant | 12/27 | 5 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
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32
GnomAD3 exomes AF: 0.00000402 AC: 1AN: 248924Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135100
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135100
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GnomAD4 exome Cov.: 32
GnomAD4 exome
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32
GnomAD4 genome Cov.: 32
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Hypertrophic cardiomyopathy Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Mar 05, 2013 | proposed classification - variant undergoing re-assessment, contact laboratory - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Feb 23, 2023 | This sequence change creates a premature translational stop signal (p.Met348Thrfs*4) 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 (rs730880336, gnomAD 0.006%). This premature translational stop signal has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 23711808, 27532257, 29907873). ClinVar contains an entry for this variant (Variation ID: 177698). 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 | Feb 03, 2017 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Mar 24, 2017 | The c.1038_1042dupCGGCA pathogenic variant in the MYBPC3 gene has been previously reported in at least one Chinese family in association with HCM and was absent from 200 control alleles (Xie et al., 2005; Pan et al., 2006; Liu et al., 2013). It is also reported as a pathogenic variant in ClinVar by at least one other clinical laboratory in association with HCM (ClinVar SCV000203958.3; Landrum et al., 2016). This variant causes a shift in reading frame starting at codon Methionine 348, changing it to a Threonine, and creating a premature stop codon at position 4 of the new reading frame, denoted p.Met348ThrfsX4. This pathogenic variant is expected to result in either an abnormal, truncated protein product or loss of protein from this allele through nonsense-mediated mRNA decay. Multiple other downstream frameshift variants in the MYBPC3 gene have been reported in HGMD in association with HCM (Stenson et al., 2014). Furthermore, c.1038_1042dupCGGCA was not observed in approximately 6,400 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. In summary, c.1038_1042dupCGGCA in the MYBPC3 gene is interpreted as a pathogenic variant. - |
Left ventricular noncompaction Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute | - | - - |
Computational scores
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at