rs397516047
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Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000256.3(MYBPC3):c.431_432del(p.Gly144AlafsTer8) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000711 in 1,406,688 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 33)
Exomes 𝑓: 7.1e-7 ( 0 hom. )
Consequence
MYBPC3
NM_000256.3 frameshift
NM_000256.3 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 0.228
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 11-47350086-GAC-G is Pathogenic according to our data. Variant chr11-47350086-GAC-G is described in ClinVar as [Pathogenic]. Clinvar id is 42749.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-47350086-GAC-G is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MYBPC3 | NM_000256.3 | c.431_432del | p.Gly144AlafsTer8 | frameshift_variant | 4/35 | ENST00000545968.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MYBPC3 | ENST00000545968.6 | c.431_432del | p.Gly144AlafsTer8 | frameshift_variant | 4/35 | 5 | NM_000256.3 | P4 | |
MYBPC3 | ENST00000399249.6 | c.431_432del | p.Gly144AlafsTer8 | frameshift_variant | 4/34 | 5 | A2 | ||
MYBPC3 | ENST00000544791.1 | c.431_432del | p.Gly144AlafsTer8 | frameshift_variant, NMD_transcript_variant | 4/27 | 5 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 genomes
?
Cov.:
33
GnomAD4 exome AF: 7.11e-7 AC: 1AN: 1406688Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 694692
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GnomAD4 genome ? Cov.: 33
GnomAD4 genome
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33
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Hypertrophic cardiomyopathy Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jul 18, 2022 | For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 42749). This premature translational stop signal has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 25611685, 27532257). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Gly144Alafs*8) 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 | May 10, 2012 | The Gly144fs variant in MYBPC3 has not been reported in the literature nor previ ously identified by our laboratory out of >3500 individuals (>2100 Caucasian; LM M unpublished data). This low frequency supports a pathogenic role. This framesh ift variant is predicted to alter the protein?s amino acid sequence beginning at position 144 and lead to a premature termination codon 8 amino acids downstream . This alteration is then predicted to lead to a truncated or absent protein. He terozygous loss of function of function of the MYBPC3 gene is an established dis ease mechanism in HCM patients. In summary, this variant meets our criteria to b e classified as pathogenic (http://pcpgm.partners.org/LMM). - |
Hypertrophic cardiomyopathy 4 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München | Jul 07, 2023 | - - |
Computational scores
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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