rs397515933
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000256.3(MYBPC3):c.1892del(p.Phe631SerfsTer32) 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. F631F) 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: 8.89
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 11-47341142-GA-G is Pathogenic according to our data. Variant chr11-47341142-GA-G is described in ClinVar as [Pathogenic]. Clinvar id is 42580.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-47341142-GA-G is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MYBPC3 | NM_000256.3 | c.1892del | p.Phe631SerfsTer32 | frameshift_variant | 19/35 | ENST00000545968.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MYBPC3 | ENST00000545968.6 | c.1892del | p.Phe631SerfsTer32 | frameshift_variant | 19/35 | 5 | NM_000256.3 | P4 | |
MYBPC3 | ENST00000399249.6 | c.1892del | p.Phe631SerfsTer32 | frameshift_variant | 18/34 | 5 | A2 | ||
MYBPC3 | ENST00000544791.1 | c.1892del | p.Phe631SerfsTer32 | 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:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Sep 06, 2017 | The c.1892delT pathogenic variant in the MYBPC3 gene has been reported in association with hypertrophic cardiomyopathy (HCM) (Ho et al., 2017; Walsh et al., 2017). Furthermore, this variant has been classified as a pathogenic variant by another clinical laboratory in ClinVar (SCV000059096.4; Landrum et al., 2016). This variant causes a shift in reading frame starting at codon phenylalanine 631, changing it to a serine, and creating a premature stop codon at position 32 of the new reading frame, denoted p.Phe631SerfsX32. 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. Other frameshift variants in the MYBPC3 gene have been reported in Human Gene Mutation Database in association with cardiomyopathy (Stenson et al., 2014), indicating that loss of function is a mechanism of disease for this gene. Furthermore, the c.1892delT variant has not been observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). - |
Hypertrophic cardiomyopathy Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Dec 27, 2011 | The Phe631fs variant has not been previously reported, but has been identified i n 1 individual with HCM out of >1950 Caucasian probands (>3900 chromosomes) test ed by our laboratory. This low frequency is consistent with a pathogenic role. T his variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 631 and leads to a premature stop codon 32 ami no acids downstream. This alteration is then predicted to lead to a truncated or absent protein (loss-of-function). Loss-of-function of the MYBPC gene is an est ablished disease mechanism and typically leads to HCM, which is consistent with the phenotype of the proband tested by our laboratory. Therefore, this variant m eets our criteria for pathogenicity based on low frequency and predicted impact on the protein (http://pcpgm.partners.org/LMM). - |
Computational scores
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Calibrated prediction
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Prediction
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