11-47347856-C-T
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong
The NM_000256.3(MYBPC3):c.821+1G>A variant causes a splice donor, intron change. The variant allele was found at a frequency of 0.00000511 in 1,564,892 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 16 ACMG points.
Transcripts
RefSeq
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| MYBPC3 | ENST00000545968.6 | c.821+1G>A | splice_donor_variant, intron_variant | Intron 7 of 34 | 5 | NM_000256.3 | ENSP00000442795.1 | |||
| MYBPC3 | ENST00000399249.6 | c.821+1G>A | splice_donor_variant, intron_variant | Intron 7 of 33 | 5 | ENSP00000382193.2 | ||||
| MYBPC3 | ENST00000544791.1 | n.821+1G>A | splice_donor_variant, intron_variant | Intron 7 of 26 | 5 | ENSP00000444259.1 |
Frequencies
GnomAD3 genomes 0.00000657 AC: 1AN: 152186Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000289 AC: 5AN: 172994Hom.: 0 AF XY: 0.0000540 AC XY: 5AN XY: 92562
GnomAD4 exome AF: 0.00000496 AC: 7AN: 1412706Hom.: 0 Cov.: 33 AF XY: 0.00000716 AC XY: 5AN XY: 698110
GnomAD4 genome 0.00000657 AC: 1AN: 152186Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74346
ClinVar
Submissions by phenotype
not provided Pathogenic:9
Reported in association with HCM, with several individuals presenting with features of HCM before 30 years of age (Niimura et al., 1998; Erdmann et al., 2001; Erdmann et al., 2003; Olivotto et al., 2008; Bashyam et al., 2012; Coppini et al., 2014; Kapplinger et al., 2014; Viswanathan et al., 2017; Lu et al., 2018; Marschall et al., 2019); Not observed at significant frequency in large population cohorts (gnomAD); Reported to destroy canonical splice donor site of intron 7 and lead to two aberrant splice transcripts, resulting in the skipping of either exon 7 alone, or exons 7 and 8; both transcripts result in a frameshift and premature stop codon in exon 9 (Erdmann et al., 2001).; Multiple other splice site variants in the MYBPC3 gene have been reported in HGMD in association with HCM (HGMD); 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; This variant is associated with the following publications: (PMID: 26914223, 28750076, 31737537, 25525159, 25524337, 21959974, 21415409, 18533079, 22267749, 9562578, 12974739, 27532257, 29121657, 30165862, 19574547, 31028938, 15519027, 11499718, 32344918, 33190526, 26582918, 24510615, 11499719) -
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Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. MYBPC3 IVS7+1G>A This variant has been seen in at least three presumably unrelated cases of HCM. Segregation of the variant with the disease within families suggests identical descent. Erdmann et al (2001) reported the variant in 2 apparently unrelated patients of European descent. It was identified in the first patient, a male whose age of onset was 38, and then was discovered in his two brothers, who had severe disease manifestations before the ages of 30. The variant was also found in their mother, who started exhibiting symptoms at age 59 but whose phenotype was less severe than her sons. The other patient who was a male, presented with HCM at the age of 24 with severe hypertrophy, angina pectoris and dyspnea and died suddenly at the age of 54. This splicing variant led to 2 aberrant RNA transcripts which skipped either exon 7 or both exon 7 and 8. Both transcripts led to frame shifts and premature stop codons on exon 9. (Erdmann et al., 2001) Haplotype analysis across the MYBPC3 locus in the relevant families revealed that all of the individuals who carried this same variant also shared either a disease-associated haplotype or a haplotype that was assumed to be disease- associated, suggesting descent from a common ancestor. (Erdmann et al., 2001) -
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Hypertrophic cardiomyopathy 4 Pathogenic:4
This variant has been identified by standard clinical testing. Selected ACMG criteria: Pathogenic (I):PP5;PM2;PVS1 -
This sequence change in MYBPC3 occurs within the canonical splice donor site of intron 7. It is predicted to cause skipping of biologically relevant exon 7/35, resulting in a frameshift leading to nonsense-mediated decay in a gene in which loss-of-function is an established disease mechanism (PMID: 7493026, 9048664, 9562578, 17823372). An RNA splicing assay of individuals with the variant confirms this prediction, demonstrating the skipping of exon 7 and exons 7 and 8 (PMID: 11499719 ). The highest population minor allele frequency in the population database gnomAD v4.1 is 0.002% (2/84,768 alleles) in the South Asian population, consistent with hypertrophic cardiomyopathy (HCM). This is a recurrent variant in individuals with HCM and segregates with disease in multiple families (PMID: 9562578, 11499719, 37652022, 38094187). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.7.0, this variant is classified as PATHOGENIC. Following criteria are met: PVS1, PP1_Strong, PM2_Supporting. -
Canonical splice site: predicted to alter splicing and result in a loss or disruption of normal protein function through protein truncation. Multiple pathogenic variants are reported in the predicted truncated region (PVS1_VS). The variant has been reported at least twice as pathogenic/likely pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000042791). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000029, PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -
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Hypertrophic cardiomyopathy Pathogenic:4
The c.821+1G>A variant in MYBPC3 has been previously reported in at least 3 indi viduals with HCM and segregated with disease in 7 affected relatives from 2 fami lies (Nimura 1998, Erdmann 2001, VanDriest 2004). This variant has also been ide ntified by our laboratory in 5 other individuals with HCM and segregated with di sease in 2 affected relatives from one family. Data from large population studi es are insufficient to assess the frequency of this variant in the general popul ation. This variant occurs in the invariant region (+/- 1,2) of the splice conse nsus sequence and has been demonstrated to cause altered splicing (Erdmann 2001) . In summary, this variant meets our criteria to be classified as pathogenic (h ttp://pcpgm.partners.org/LMM) based upon consistency with the established diseas e causing mechanism. -
The c.821+1G>A variant in the MYBPC3 gene is located in intron 7 at the canonical donor splice site. It is predicted to result in splice donor loss (SpliceAI delta score: 0.87), and disrupted splicing and an aberrant or absent protein product. This variant has been identified in multiple unrelated individuals with hypertrophic cardiomyopathy (PMID: 35176171, 28750076, 33190526, 21959974, 31941943, 12974739, 11499719, 30165862). Loss-of-function variants in MYBPC3 are known to be pathogenic (PMID: 23816408, 7493025, 19574547). Experimental RNA analysis from patient lymphocytes has shown that this variant results in aberrant transcripts due to exon-skipping and frameshift leading to premature stop codon (PMID: 11499719). The variant is reported in ClinVar (ID: 42791). The variant is rare in the general population according to gnomAD (5/172994 chromosomes). Therefore, the c.821+1G>A variant in the MYBPC3 gene has been classified as pathogenic. -
This sequence change affects a donor splice site in intron 7 of the MYBPC3 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or altered protein product. This variant is present in population databases (rs397516073, gnomAD 0.009%). Disruption of this splice site has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 9562578, 11499718, 11499719, 15519027, 26914223). It has also been observed to segregate with disease in related individuals. This variant is also known as Int8DSG+1A and IVS7+1G>A. ClinVar contains an entry for this variant (Variation ID: 42791). Studies have shown that disruption of this splice site results in skipping of exon 7 alone or skipping of exons 7 and 8, and produces a non-functional protein and/or introduces a premature termination codon (PMID: 11499719). For these reasons, this variant has been classified as Pathogenic. -
This variant (also known as IVS7+1G>A and as Int8DSG+1A) alters the intron 7 canonical splice donor site of the MYBPC3 gene. Functional RNA studies have shown that this variant causes causes skipping of exon 7, or exons 7 and 8 leading to frameshift and a premature stop codon in exon 9 (PMID: 11499719). This variant has been reported in over 10 unrelated individuals affected with hypertrophic cardiomyopathy (PMID: 9562578, 11499718, 11499719, 21959974, 24510615, 26914223, 27532257, 29121657, 30165862; Color internal data). It has been reported to segregate with disease in multiple affected individuals from two families (PMID: 9562578, 11499719). This variant has also been reported in an infant affected with sudden unexplained death (PMID: 35027292) and in an individual affected with dilated cardiomyopathy (PMID: 35581137). This variant has been identified in 5/172994 chromosomes 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. -
Cardiomyopathy Pathogenic:2
This variant (also known as IVS7+1G>A and as Int8DSG+1A) alters the intron 7 canonical splice donor site of the MYBPC3 gene. Functional RNA studies have shown that this variant causes causes skipping of exon 7, or exons 7 and 8 leading to frameshift and a premature stop codon in exon 9 (PMID: 11499719). This variant has been reported in over 10 unrelated individuals affected with hypertrophic cardiomyopathy (PMID: 9562578, 11499718, 11499719, 21959974, 24510615, 26914223, 27532257, 29121657, 30165862; Color internal data). It has been reported to segregate with disease in multiple affected individuals from two families (PMID: 9562578, 11499719). This variant has also been reported in an infant affected with sudden unexplained death (PMID: 35027292) and in an individual affected with dilated cardiomyopathy (PMID: 35581137). This variant has been identified in 5/172994 chromosomes 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. -
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Primary familial hypertrophic cardiomyopathy Pathogenic:2
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Variant summary: MYBPC3 c.821+1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 5' splicing donor site. At least one publication reports experimental evidence that this variant affects mRNA splicing leading to two aberrant transcripts with skipping of either exon 7 alone or exons 7 and 8. Both transcripts led to frame shifts and premature stop codons in exon 9 (Erdmann_2001). The variant allele was found at a frequency of 2.9e-05 in 172994 control chromosomes. c.821+1G>A has been reported in the literature in multiple individuals affected with Hypertrophic Cardiomyopathy (Niimura_1998, Erdmann_2001, Murphy_2016, Viswanathan_2018). These data indicate that the variant is very likely to be associated with disease. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Left ventricular noncompaction 10 Pathogenic:1
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SUDDEN INFANT DEATH SYNDROME Pathogenic:1
We classify this variant as pathogenic using the following ACMG/AMP criteria: PS3, PVS1, PP1, PP5 -
Primary dilated cardiomyopathy Pathogenic:1
This sequence change results in a frameshift variant in the MYBPC3 gene resulting in loss-of function and haploinsufficiency, which is a known disease mechanism(PVS1). The variant affects a highly conserved nucleotide in the splice donor consensus sequence, inactivating this donor site. Several prediction programs expect an effect on splicing (PP3) (SpliceSiteFinder-Like; MaxEntScan, NNSPLICE;Human SplicingFinder). The splicing was confirmed by the presence of exon-7 skipping on cDNA from patient lymphocytes. The aberrant cDNA resulted in a frameshift and a premature termination of translation resulting in a large truncated protein (-80%) lacking the MyBP-C motif containing the phosphorylation sites and the titin and myosin binding sites (PMID: 9048664). This variant is present in population databases (GnomAD 5/ 172994). This variant has been reported in the literature in several families with HCM and showed co-seggregation with HCM in three distinct families (PP1strong) (PMID: 9562578; PMID: 11499719; PMID: 15519027; PMID: 12707239). We identified this variant in a DCM patient and a patients with HCM. In conclusion this variant was classified as a pathogenic variant according to ACMG-guidelines (PVS1; PP1strong;PP3). -
Cardiovascular phenotype Pathogenic:1
The c.821+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 7 of the MYBPC3 gene. This alteration has been reported in multiple families with hypertrophic cardiomyopathy (HCM) and segregated with disease (Niimura H et al. N Engl J Med. 1998;338(18):1248-57; Erdmann J et al. J Am Coll Cardiol. 2001;38(2):322-30). This alteration was also observed in HCM testing cohorts; however, clinical details were limited (Kapplinger JD et al. J Cardiovasc Transl Res. 2014;7(3):347-61; Walsh R et al. Genet. Med., 2017 Feb;19:192-203). In one study, mRNA analysis showed this alteration led to skipping of either exon 7 alone or exons 7 and 8, and both abnormal transcripts resulted in frameshifts and premature stop codons in exon 9 (Erdmann J et al. J Am Coll Cardiol. 2001;38(2):322-30). 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. In addition to the clinical and functional 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. -
MYBPC3-related disorder Pathogenic:1
The MYBPC3 c.821+1G>A variant is predicted to disrupt the GT donor site and interfere with normal splicing. This variant was reported in multiple patients with hypertrophic cardiomyopathy (Niimura et al. 1998. PubMed ID: 9562578; Table S1A, Walsh et al. 2017. PubMed ID: 27532257; Lu et al. 2018. PubMed ID: 30165862; O'Hare et al. 2020. PubMed ID: 33190526). mRNA studies in patients’ lymphocytes confirmed the aberrant splicing (Erdmann et al. 2001. PubMed ID: 11499719). This variant is reported in 0.0081% of alleles in individuals of East Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/11-47369407-C-T). Variants that disrupt the consensus splice donor site in MYBPC3 are expected to be pathogenic. This variant is interpreted as pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at