11-47332813-C-T
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000256.3(MYBPC3):c.3490+1G>A variant causes a splice donor, intron change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Consequence
NM_000256.3 splice_donor, intron
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.3490+1G>A | splice_donor_variant, intron_variant | Intron 31 of 34 | 5 | NM_000256.3 | ENSP00000442795.1 | |||
| MYBPC3 | ENST00000399249.6 | c.3490+1G>A | splice_donor_variant, intron_variant | Intron 30 of 33 | 5 | ENSP00000382193.2 |
Frequencies
GnomAD3 genomes
GnomAD4 exome Cov.: 34
GnomAD4 genome
ClinVar
Submissions by phenotype
Hypertrophic cardiomyopathy 4 Pathogenic:2
MYBPC3 c.3490+1G>A has been previously reported in at least 4 HCM cases (Walsh R, et al., 2017; Weissler-Snir A, et al., 2017; Ehlermann P, et al., 2008; Rottbauer W, et al., 1997) and was found to segregate to multiple affected individuals in 2 families (Ehlermann P, et al., 2008; Rottbauer W, et al., 1997). We identified this variant in 2 HCM probands (1 North-West European descent, 1 Aboriginal), both of whom have no family history of disease. The variant is absent in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/), as well as the Genome Aggregation Database (http://gnomad.broadinstitute.org/). In silico tool MaxEntScan predicts that the variant will affect splicing. In summary, based on multiple reports in HCM cases, strong segregation in affected individuals, rarity of the variant in the general population and because MYBPC3 loss of function variants are an established cause of HCM, we classify MYBPC3 c.3490+1G>A as 'Pathogenic'. -
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Hypertrophic cardiomyopathy Pathogenic:2
The 3490+1 G>A variant in MYBPC3 has been identified an individual with HCM, seg regated with disease in 4 affected relatives and was absent from 3 unaffected re latives as well as 500 control chromosomes (Rottbauer 1997). This variant occurs in the invariant region (+/- 1,2) of the splice consensus sequence and results in exon skipping, leading to a frameshift and premature termination codon (Rottb auer 1997), which is predicted to lead to an abnormal or absent protein. Loss of function of the MYBPC3 gene is an established mechanism of disease for HCM. In summary, this variant meets our criteria to be classified as pathogenic (http:// pcpgm.partners.org/LMM) based upon the severe impact of the protein. -
This sequence change affects a donor splice site in intron 31 of the MYBPC3 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in MYBPC3 are known to be pathogenic (PMID: 19574547). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 9218526, 27532257). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 42715). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -
not provided Pathogenic:1
Published functional studies demonstrate abnormal gene splicing with exon skipping (Rottbauer et al., 1997); Reported in ClinVar as a pathogenic variant (ClinVar Variant ID# 42715; Landrum et al., 2016); Canonical splice site variant predicted to result in a null allele in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 28790153, 28193612, 27532257, 9218526) -
Cardiovascular phenotype Pathogenic:1
The c.3490+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 31 of the MYBPC3 gene. This variant has been detected in unrelated individuals with hypertrophic cardiomyopathy (HCM) and has been reported to segregate with HCM in families (Rottbauer W et al. J Clin Invest, 1997 Jul;100:475-82; Ross SB et al. Circ Cardiovasc Genet, 2017 Jun;10; Weissler-Snir A et al. Circ Cardiovasc Imaging, 2017 Feb;10; Walsh R et al. Genet Med, 2017 Feb;19:192-203;Chung H et al. J Cardiovasc Magn Reson, 2021 Mar;23:18; Burstein DS et al. Pediatr Res, 2021 May;89:1470-1476). RNA studies performed on samples from carriers of this variant have indicated that this variant results in exon skipping (Rottbauer W et al. J Clin Invest, 1997 Jul;100:475-82). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site and will result in the creation or strengthening of a novel splice donor site. In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as a disease-causing mutation. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at