chr11-47347065-C-T
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP5
The NM_000256.3(MYBPC3):​c.906-36G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000014 in 715,268 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_000256.3 intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 3 ACMG points.
Transcripts
RefSeq
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| MYBPC3 | ENST00000545968.6 | c.906-36G>A | intron_variant | Intron 9 of 34 | 5 | NM_000256.3 | ENSP00000442795.1 | |||
| MYBPC3 | ENST00000399249.6 | c.905+361G>A | intron_variant | Intron 9 of 33 | 5 | ENSP00000382193.2 | ||||
| MYBPC3 | ENST00000544791.1 | n.906-36G>A | intron_variant | Intron 9 of 26 | 5 | ENSP00000444259.1 |
Frequencies
GnomAD3 genomes
GnomAD4 exome AF: 0.00000140 AC: 1AN: 715268Hom.: 0 Cov.: 9 AF XY: 0.00 AC XY: 0AN XY: 383492
GnomAD4 genome
ClinVar
Submissions by phenotype
Hypertrophic cardiomyopathy 4 Pathogenic:3
The variant has been previously reported as de novo in a similarly affected individual (PMID: 29355681, PS2_S). In silico prediction tools predicted that this variant influenced pre-mRNA splicing, resulting in aberrant splicing (SPLICEAI: 0.91, PP3_P). The variant has been reported at least twice as pathogenic/likely pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000219660, 3billion dataset). It is not observed in the gnomAD v2.1.1 dataset (PM2_M). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline. -
The heterozygous c.906-36G>A variant in MYBPC3 was identified by our study in one individual with familial hypertrophic cardiomyopathy. Computational prediction tools and conservation analyses suggest that this variant may impact splicing, though this information is not predictive enough to determine pathogenicity. In vitro functional studies provide some evidence that the c.906-36G>A variant may impact protein function by creating an acceptor splice site and a 34 nucleotide insertion in the transcript, leading to a frameshift in Exon 10 and premature termination codon in Exon 12 (PMID: 18337725). However, these types of assays may not accurately represent biological function.This variant was absent from large population studies. This variant has been reported pathogenic and was reported to cosegregate with familial hypertrophic cardiomyopathy in one family in ClinVar (Variation ID: 219660) and was reported in the homozygous state in one unrelated individual with hypertrophic cardiomyopathy (PMID: 18337725). In summary, although additional studies are required to fully establish its clinical significance, the c.906-36G>A variant is likely pathogenic. ACMG/AMP Criteria applied: PM2, PS3, PP1, PP3 (Richards 2015). -
Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Likely Pathogenic. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. (N) 0108 - This gene is known to be associated with both recessive and dominant disease. (N) 0112 - Variants in this gene are known to have reduced penetrance (OMIM). (N) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein. (P) 0210 - Splice site variant (canonical or non-canonical) proven to affect splicing/expression of the transcript with a known effect on protein structure. This variant has been shown to activate a cryptic splice site, resulting in an inclusion of 34 nt of intron 9 into exon 10. This insertion produces a frameshift resulting in a premature termination codon in exon 12 (PMID: 18337725). (N) 0251 - Variant is heterozygous. (N) 0301 - Variant is absent from gnomAD. (P) 0508 - In-silico predictions for abnormal splicing are conflicting. (N) 0701 - Comparable variants have very strong previous evidence for pathogenicity. Other variants predicted to cause NMD have been reported in ClinVar as pathogenic. (P) 0802 - Moderate previous evidence of pathogenicity in unrelated individuals. The variant has been previously reported as pathogenic in patients with hypertrophic cardiomyopathy (ClinVar, PMID: 18337725, 31730716). (P) 1007 - No published functional evidence has been identified for this variant. (N) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign -
not provided Pathogenic:2Uncertain:1
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Not observed at significant frequency in large population cohorts (Lek et al., 2016); Non-canonical splice site variant demonstrated to result in loss-of-function; published functional mRNA studies demonstrate that this variant creates a de novo splice acceptor site in intron 9 and leads to abnormal gene splicing which results in the inclusion of an additional 34 nucleotides of intron 9 into the MYBPC3 mRNA (Frank-Hansen et al., 2008); Reported in ClinVar as pathogenic and noted to segregate with disease in a family by another clinical laboratory (ClinVar Variant ID 219660; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 31730716, 29998127, 12974739, 18337725, 30297972, 22267749, 32396390, 27535533) -
MYBPC3: PM2, PS4:Moderate, PP3 -
Cardiomyopathy Pathogenic:2
This variant causes a G to A nucleotide substitution at the -36 position of intron 9 of the MYBPC3 gene. A RT-PCR study using cells from a carrier individual has shown that this variant creates a new splice acceptor site and causes the inclusion of 34 nucleotides of intron 9 into exon 10, leading to a frameshift in exon 10 and premature termination codon in exon 12 (PMID: 18337725). This mutant transcript is expected to result in an absent or non-functional protein product. This variant has been reported in up to seven unrelated individuals affected with hypertrophic cardiomyopathy, as well as in a mother and a daughter from one family affected with hypertrophic cardiomyopathy (PMID: 18337725, 31730716; Clinvar variation ID: 219660; communication with an external laboratory). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -
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Hypertrophic cardiomyopathy Pathogenic:2
This sequence change falls in intron 9 of the MYBPC3 gene. It does not directly change the encoded amino acid sequence of the MYBPC3 protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or altered protein product. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individuals with hypertrophic cardiomyopathy (PMID: 18337725, 31730716; internal data). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 219660). Studies have shown that this variant results in creation of a de novo splice acceptor, and produces a non-functional protein and/or introduces a premature termination codon (PMID: 18337725). For these reasons, this variant has been classified as Pathogenic. -
The c.906-36G>A variant in MYBPC3 has been reported in at least 6 individuals with hypertrophic cardiomyopathy (HCM) and segregated with disease in 1 affected individual (Frank-Hansen 2008 PMID:18337725, Janin 2020 PMID: 31730716 , ClinVar: SCV000259662). It was absent from large population studies, but has been reported in ClinVar (Variation ID: 219660). This variant is located in the 3' splice region. Computational tools and in vitro studies with patient leukocytes predict a splicing impact, though this information is not predictive enough to determine pathogenicity (Frank-Hansen 2008 PMID:18337725). In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant HCM. ACMG/AMP Criteria applied: PM2, PS3_Moderate, PS4_Moderate. -
Cardiovascular phenotype Pathogenic:1
The c.906-36G>A intronic pathogenic mutation results from a G to A substitution 36 nucleotides upstream from coding exon 10 in the MYBPC3 gene. This alteration (also referred to as IVS9-36G>A) has been reported in multiple individuals in hypertrophic cardiomyopathy (HCM) cohorts, and RNA studies revealed aberrant splicing resulting in premature protein truncation (Erdmann J et al. Clin Genet, 2003 Oct;64:339-49; Frank-Hansen R et al. Eur. J. Hum. Genet., 2008 Sep;16:1062-9; Salman OF et al. Front Cardiovasc Med, 2018 Jun;5:77; Janin A et al. Hum Mutat, 2020 02;41:465-475; Lopes LR et al. Circ Genom Precis Med, 2020 06;13:e002905, Ambry internal data). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -
MYBPC3-related disorder Pathogenic:1
The MYBPC3 c.906-36G>A variant is predicted to interfere with splicing. This variant was reported in at least five unrelated individuals with hypertrophic cardiomyopathy (Erdmann et al. 2003. PubMed ID: 12974739; Frank-Hansen et al. 2008. PubMed ID: 18337725; Janin et al. 2020. PubMed ID: 31730716; Lopes et al. 2020. PubMed ID: 32396390). RNA studies on the affected individual’s peripheral blood leukocytes showed that this variant resulted in the inclusion of 34 nucleotides of intron 9 and a subsequent frameshift and premature protein termination (Frank-Hansen et al. 2008. PubMed ID: 18337725). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at