rs727504335
Positions:
Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1PM2PM4_Supporting
The NM_000256.3(MYBPC3):c.239delinsGAGG(p.Ala80delinsGlyGly) variant causes a protein altering 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 Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. A80A) has been classified as Likely benign.
Frequency
Genomes: not found (cov: 32)
Consequence
MYBPC3
NM_000256.3 protein_altering
NM_000256.3 protein_altering
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 7.41
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 Uncertain_significance. Variant got 5 ACMG points.
PM1
?
In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 uncertain in NM_000256.3
PM2
?
Very rare variant in population databases, with high coverage;
PM4
?
Nonframeshift variant in NON repetitive region in NM_000256.3. Strenght limited to Supporting due to length of the change: 1aa.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MYBPC3 | NM_000256.3 | c.239delinsGAGG | p.Ala80delinsGlyGly | protein_altering_variant | 2/35 | ENST00000545968.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MYBPC3 | ENST00000545968.6 | c.239delinsGAGG | p.Ala80delinsGlyGly | protein_altering_variant | 2/35 | 5 | NM_000256.3 | P4 | |
MYBPC3 | ENST00000399249.6 | c.239delinsGAGG | p.Ala80delinsGlyGly | protein_altering_variant | 2/34 | 5 | A2 | ||
MYBPC3 | ENST00000544791.1 | c.239delinsGAGG | p.Ala80delinsGlyGly | protein_altering_variant, NMD_transcript_variant | 2/27 | 5 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome Cov.: 36
GnomAD4 exome
Cov.:
36
GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jan 23, 2013 | proposed classification - variant undergoing re-assessment, contact laboratory - |
Cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jun 20, 2023 | This variant causes an in-frame deletion of one amino acid and insertion of two amino acids at exon 2 of the MYBPC3 protein. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in one individual affected with dilated cardiomyopathy (PMID: 22464770, 27532257). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
Hypertrophic cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 13, 2024 | This variant, c.239delinsGAGG, is a complex sequence change that results in the deletion of 1 and insertion of 2 amino acid(s) in the MYBPC3 protein (p.Ala80delinsGlyGly). This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with dilated cardiomyopathy (DCM) (PMID: 22464770, 27532257). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 22, 2022 | The c.239delCinsGAGG variant (also known as p.A80delinsGG), located in coding exon 2 of the MYBPC3 gene, results from an in-frame deletion of C and insertion of GAGG at nucleotide position 239. This results in the substitution of a highly conserved alanine residue at codon 80 for two glycine residues. This alteration has been detected in an individual from a dilated cardiomyopathy cohort (Lakdawala NK et al. J. Card. Fail., 2012 Apr;18:296-303; Pugh TJ et al. Genet. Med. 2014 Aug;16(8):601-8; Walsh R et al. Genet. Med., 2017 Feb;19:192-203). In addition, the in silico prediction for this alteration is inconclusive (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at