rs727505152
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000256.3(MYBPC3):c.1330del(p.Ser444AlafsTer6) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. 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: 33)
Consequence
MYBPC3
NM_000256.3 frameshift
NM_000256.3 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 1.66
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 11-47343041-CT-C is Pathogenic according to our data. Variant chr11-47343041-CT-C is described in ClinVar as [Pathogenic]. Clinvar id is 179821.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.1330del | p.Ser444AlafsTer6 | frameshift_variant | 15/35 | ENST00000545968.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MYBPC3 | ENST00000545968.6 | c.1330del | p.Ser444AlafsTer6 | frameshift_variant | 15/35 | 5 | NM_000256.3 | P4 | |
MYBPC3 | ENST00000399249.6 | c.1330del | p.Ser444AlafsTer6 | frameshift_variant | 14/34 | 5 | A2 | ||
MYBPC3 | ENST00000544791.1 | c.1330del | p.Ser444AlafsTer6 | frameshift_variant, NMD_transcript_variant | 15/27 | 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 | Oct 24, 2022 | For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 179821). This premature translational stop signal has been observed in individual(s) with clinical features of MYBPC3-related conditions (PMID: 31737537). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Ser444Alafs*6) 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). - |
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jun 17, 2014 | The Ser444fs variant in MYBPC3 has not been previously reported in individuals w ith cardiomyopathy or in large population studies. This frameshift variant is pr edicted to alter the protein?s amino acid sequence beginning at position 444 and lead to a premature termination codon 6 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Heterozygous loss o f function of the MYBPC3 gene is an established disease mechanism in HCM. In sum mary, this variant meets our criteria to be classified as pathogenic (http://pcp gm.partners.org/LMM) based upon the predicted impact of the variant. - |
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