rs727503172
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000256.3(MYBPC3):c.3288delG(p.Glu1096AspfsTer93) 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. E1096E) has been classified as Benign. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_000256.3 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| MYBPC3 | ENST00000545968.6 | c.3288delG | p.Glu1096AspfsTer93 | frameshift_variant | Exon 30 of 35 | 5 | NM_000256.3 | ENSP00000442795.1 | ||
| MYBPC3 | ENST00000399249.6 | c.3288delG | p.Glu1096AspfsTer93 | frameshift_variant | Exon 29 of 34 | 5 | ENSP00000382193.2 |
Frequencies
GnomAD3 genomes
GnomAD4 exome Cov.: 56
GnomAD4 genome
ClinVar
Submissions by phenotype
Hypertrophic cardiomyopathy Pathogenic:4
This sequence change creates a premature translational stop signal (p.Glu1096Aspfs*93) 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). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 2732257, 16679492, 21750094, 24510615). ClinVar contains an entry for this variant (Variation ID: 164042). For these reasons, this variant has been classified as Pathogenic. -
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The p.Glu1096fs variant in MYBPC3 has been identified in 5 individuals with HCM (Lekanne Deprez 2006, Kapplinger 2014, LMM unpublished data). It was absent from large population studies. This variant is predicted to cause a frameshift, whic h alters the protein?s amino acid sequence beginning at position 1096 and lead t o a premature termination codon 93 amino acids downstream. This alteration is th en predicted to lead to a truncated or absent protein. Heterozygous loss of func tion of the MYBPC3 gene is an established disease mechanism in HCM. In summary, this variant meets our criteria to be classified as pathogenic (http://www.partn ers.org/personalizedmedicine/LMM) based upon the predicted impact of the variant . -
This variant deletes 1 nucleotide in exon 30 of the MYBPC3 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in at least five individuals affected with hypertrophic cardiomyopathy (PMID: 21750094, 24793961, 25611685, 27532257, 30297972, 30847666). It has also been reported in compound heterozygous state with another pathogenic truncation variant in the MYBPC3 gene in one infant affected with severe neonatal hypertrophic cardiomyopathy (PMID: 16679492). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of MYBPC3 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. -
not provided Pathogenic:3
Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Published RNA studies demonstrate mRNA nonsense mediated decay and absence of protein (PMID: 16679492); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 30847666, 21750094, 16679492, 27532257, 24510615) -
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Hypertrophic cardiomyopathy 4 Pathogenic:2
_x000D_ Criteria applied: PVS1, PS4_MOD, PM2_SUP -
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Cardiomyopathy Pathogenic:1
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Primary familial hypertrophic cardiomyopathy Pathogenic:1
Variant summary: MYBPC3 c.3288delG (p.Glu1096AspfsX93) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 210992 control chromosomes. c.3288delG has been reported in the literature in multiple individuals affected with Hypertrophic Cardiomyopathy (examples- Lekanne_2006, Waldmuller_2011, Kapplinger_2014, Bos_2014, Walsh_2017, van Lint_2019). These data indicate that the variant is very likely to be associated with disease, however at least one publication reports the variant in an unaffected individual, suggesting imcomplete penetrance (Lekanne_2006). One publication reports that mRNA with the variant could not be detected in the peripheral blood of a patient with this mutation, indicating nonsense-mediated decay (Lekanne_2006). Six other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, citing the variant as pathogenic (n=5) and uncertain significance (n=1). Based on the evidence outlined above, the variant was classified as pathogenic. -
Cardiovascular phenotype Pathogenic:1
The c.3288delG pathogenic mutation, located in coding exon 30 of the MYBPC3 gene, results from a deletion of one nucleotide at nucleotide position 3288, causing a translational frameshift with a predicted alternate stop codon (p.E1096Dfs*93). This alteration has been reported in individuals with hypertrophic cardiomyopathy (Lekanne Deprez RH et al. J. Med. Genet., 2006 Oct;43:829-32; Kapplinger JD et al. J Cardiovasc Transl Res, 2014 Apr;7:347-61). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at