rs876657703
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000256.3(MYBPC3):c.1444_1445insG(p.Ala482GlyfsTer49) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. A482A) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 33)
Consequence
MYBPC3
NM_000256.3 frameshift
NM_000256.3 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 7.40
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 11-47342842-G-GC is Pathogenic according to our data. Variant chr11-47342842-G-GC is described in ClinVar as [Pathogenic]. Clinvar id is 228368.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.1444_1445insG | p.Ala482GlyfsTer49 | frameshift_variant | 16/35 | ENST00000545968.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MYBPC3 | ENST00000545968.6 | c.1444_1445insG | p.Ala482GlyfsTer49 | frameshift_variant | 16/35 | 5 | NM_000256.3 | P4 | |
MYBPC3 | ENST00000399249.6 | c.1444_1445insG | p.Ala482GlyfsTer49 | frameshift_variant | 15/34 | 5 | A2 | ||
MYBPC3 | ENST00000544791.1 | c.1444_1445insG | p.Ala482GlyfsTer49 | frameshift_variant, NMD_transcript_variant | 16/27 | 5 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 genomes
?
Cov.:
33
GnomAD4 exome Cov.: 31
GnomAD4 exome
Cov.:
31
GnomAD4 genome ? Cov.: 33
GnomAD4 genome
?
Cov.:
33
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Hypertrophic cardiomyopathy Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 04, 2023 | This sequence change creates a premature translational stop signal (p.Ala482Glyfs*49) 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 not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with MYBPC3-related conditions. ClinVar contains an entry for this variant (Variation ID: 228368). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | May 01, 2015 | The p.Ala482fs variant in MYBPC3 has not been previously reported in individuals with cardiomyopathy and was absent from large population studies. This variant is predicted to cause a frameshift, which alters the protein?s amino acid sequen ce beginning at position 482 and leads to a premature termination codon 49 amino acids downstream. This alteration is then predicted to lead to a truncated or a bsent protein. Heterozygous loss of MYBPC3 function is an established disease me chanism in individuals with HCM. In summary, this variant meets our criteria to be classified as pathogenic for HCM in an autosomal dominant manner (http://www. partners.org/personalizedmedicine/LMM) based upon the predicted impact of the va riant and absence from controls. - |
Computational scores
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Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at