rs727503175
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate
The NM_000256.3(MYBPC3):c.3089_3101del(p.Leu1030ProfsTer12) 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. L1030L) 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: 8.93
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 12 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 11-47333645-GGCCCGGATGAACA-G is Pathogenic according to our data. Variant chr11-47333645-GGCCCGGATGAACA-G is described in ClinVar as [Pathogenic]. Clinvar id is 164049.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MYBPC3 | NM_000256.3 | c.3089_3101del | p.Leu1030ProfsTer12 | frameshift_variant | 29/35 | ENST00000545968.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MYBPC3 | ENST00000545968.6 | c.3089_3101del | p.Leu1030ProfsTer12 | frameshift_variant | 29/35 | 5 | NM_000256.3 | P4 | |
MYBPC3 | ENST00000399249.6 | c.3089_3101del | p.Leu1030ProfsTer12 | frameshift_variant | 28/34 | 5 | A2 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 genomes
Cov.:
33
We have no GnomAD4 exomes data on this position. Probably position not covered by the project.
GnomAD4 genome Cov.: 33
GnomAD4 genome
Cov.:
33
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Hypertrophic cardiomyopathy Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Apr 20, 2013 | The Leu1030fs variant in MYBPC3 has not been reported in individuals with cardio myopathy. This frameshift variant is predicted to alter the protein?s amino acid sequence beginning at position 1030 and lead to a premature termination codon 1 2 amino acids downstream. This alteration is then predicted to lead to a truncat ed or absent protein. Frameshift and other truncating variants in MYBPC3 are est ablished as pathogenic for HCM. In summary, this variant meets our criteria to b e classified as pathogenic (http://pcpgm.partners.org/LMM) based upon the predic ted impact of the variant. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at