rs397515931
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate
The NM_000256.3(MYBPC3):c.1863del(p.Phe621LeufsTer42) 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 (★). Synonymous variant affecting the same amino acid position (i.e. F621F) 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: -0.0190
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 11-47341171-CG-C is Pathogenic according to our data. Variant chr11-47341171-CG-C is described in ClinVar as [Pathogenic]. Clinvar id is 42578.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-47341171-CG-C is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MYBPC3 | NM_000256.3 | c.1863del | p.Phe621LeufsTer42 | frameshift_variant | 19/35 | ENST00000545968.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MYBPC3 | ENST00000545968.6 | c.1863del | p.Phe621LeufsTer42 | frameshift_variant | 19/35 | 5 | NM_000256.3 | P4 | |
MYBPC3 | ENST00000399249.6 | c.1863del | p.Phe621LeufsTer42 | frameshift_variant | 18/34 | 5 | A2 | ||
MYBPC3 | ENST00000544791.1 | c.1863del | p.Phe621LeufsTer42 | frameshift_variant, NMD_transcript_variant | 19/27 | 5 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 genomes
?
Cov.:
33
GnomAD4 exome Cov.: 36
GnomAD4 exome
Cov.:
36
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 09, 2015 | The p.Phe621fs variant in MYBPC3 has been identified by our laboratory in 2 adul ts with HCM and segregated with disease in 1 affected family member. It was abse nt from large population studies (dbSNP rs397515931). This frameshift variant is predicted to alter the protein's amino acid sequence beginning at position 621 and lead to a premature termination codon 42 amino acids downstream. This altera tion is then predicted to lead to a truncated or absent protein. Heterozygous lo ss of MYBPC3 function is an established disease mechanism in HCM. In summary, th is variant meets our criteria to be classified as pathogenic (http://www.partner s.org/personalizedmedicine/LMM) for HCM in an autosomal dominant manner based up on the predicted impact of the variant 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