rs397516083
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PP5_Very_Strong
The NM_000256.3(MYBPC3):c.927-9G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000121 in 1,568,024 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 Pathogenic (★★).
Frequency
Consequence
NM_000256.3 intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
Transcripts
RefSeq
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| MYBPC3 | ENST00000545968.6 | c.927-9G>A | intron_variant | Intron 11 of 34 | 5 | NM_000256.3 | ENSP00000442795.1 | |||
| MYBPC3 | ENST00000399249.6 | c.927-9G>A | intron_variant | Intron 10 of 33 | 5 | ENSP00000382193.2 | ||||
| MYBPC3 | ENST00000544791.1 | n.927-9G>A | intron_variant | Intron 11 of 26 | 5 | ENSP00000444259.1 |
Frequencies
GnomAD3 genomes 0.0000197 AC: 3AN: 152184Hom.: 0 Cov.: 32
GnomAD4 exome AF: 0.0000113 AC: 16AN: 1415840Hom.: 0 Cov.: 32 AF XY: 0.00000715 AC XY: 5AN XY: 699326
GnomAD4 genome 0.0000197 AC: 3AN: 152184Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74342
ClinVar
Submissions by phenotype
not provided Pathogenic:5
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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 IVS11-9G>A This variant has been seen in at least 30 presumably unrelated cases of HCM (4 published, >26 unpublished). Four of >30 patients who had another variant: -One patient with p.Arg502Trp in MYBPC3 (pathogenic), with a severe phenotype and segregation consistent with two pathogenic variants. -One patient with p.Arg278Cys (c.832C>T) in TNNT2 (ClinVar: VUS by LMM, Blueprint, CHEO, Semsarian’s group; pathogenic by GeneDx), with severe phenotype, no segregation data. -One patient with p.Asn47Lys (c.141C>A) in MYL2 (ClinVar: VUS by LMM, Blueprint; pathogenic by GeneDx), diagnosed 56yo with LVWT 24 mm. -One patient with c.2864del in MYBPC3 (not in ClinVar, not published, ERA classifies as pathogenic), diagnosed 54yo with LVWT 21 mm. There is moderate segregation data. In 5 families an additional affected relative carried this variant. In total, the variant has not been seen in at least 6326 and as many as 64,326 individuals from presumably unrelated published and database controls. Both in silico and in vitro data suggest that this variant causes aberrant splicing (Crehalet, 2012). Published cases: Rodriguez-Garcia (2010) reported this variant in 2 patients diagnosed with HCM cared for in Complejo Hospitalario Universitario A Coruña, Spain, who underwent analysis of 537 genetic variants of HCM disease genes - TNNT2, TNNI3, TPM1, MYL2, MYL3, ACTC, TTN, MYH6, MYLK2, MYO6, and TCAP. No phenotype information is provided for the two patients. Authors report 1 affected male has an affected daughter with this variant. Crehalet (2012) reported this variant in 2 patients diagnosed with HCM cared for in Bron, Lyon, and Nantes (France) who underwent sequencing analysis of MYBPC3, MYH7, TNNT2, and TNNI3 genes. One of the patients was 12-year old boy with HCM and the other was a 30-year old man with HCM and atrial fibrillation. Gruner (2014) reported this variant in one “G+/P-“ patient cared for at the Tufts Medical Center or the Toronto General Hospital. The patient is a 27-year-old woman with a normal maximum left ventricular thickness of 11 mm and no LVOT obstruction was present. Her family history was not reported. This variant is located in flanking intronic regions of intron 11. According to Crehalet et al (2012), the weak acceptor splice site of intron 11 was detected by Human Splicing Finder (HSF) which predicted the creation of a new acceptor site at position c.927-9, which is stronger than the wild type. In addition, HeLa cells transfected with the wild type sequence showed two different transcripts: a 410 bp normal product containing exon 12 and the 248 bp product corresponding to exon 12 skipping, as for the wild type minigene c.1090G, confirming that the weak acceptor site of intron 11 is not always recognized in HeLa cells. Furthermore, mutant minigene assay showed complete exon 12 skipping and the transcript lacking exon 12 would encode a truncated protein. Additional MYBPC3 splice variants reported in association with HCM include: IVS2-1G>A, IVS6-2A>C IVS7+1G>A, IVS8+1G>A, IVS12-2A>G, IVS14-2A>G, IVS16-1G>A, IVS22+1G>A, IVS24+1G>A, IVS28+1G>A, IVS32+1G>A, and IVS33+1G>A. The base is conserved across mammals with the exception of Cape golden mole (T). In total the variant has not been seen in at least 6326 and as many as 64,326 individuals from published controls and publicly available datasets that approximate the general population. The variant is absent in European American and African American populations by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS), which includes data on ~6,000 individuals of European or African American backgrounds. It is also not listed i -
Not observed at a significant frequency in large population cohorts (gnomAD); Published functional studies demonstrated that c.927-9 G>A leads to skipping of exon 12 and results in either an abnormal truncated protein or haploinsufficiency due to the creation of an unstable transcript (Helms et al., 2014; Crehalet et al., 2012); Reported in ClinVar as a pathogenic variant (ClinVar Variant ID# 42807); This variant is associated with the following publications: (PMID: 21488308, 31737537, 25217454, 27834932, 21415409, 31028938, 25031304, 24113344, 23549607, 24810389, 20433692, 27688314, 26914223, 28916354, 28790153, 29121657, 30645170, 31006259, 33673806, 31589614, 30550750, 32746448, 28679633, 31447099, 34135346) -
MYBPC3: PP1:Strong, PM2, PS3:Moderate, PS4:Moderate -
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Hypertrophic cardiomyopathy 4 Pathogenic:4
A heterozygous c.927-9G>A pathogenic variant in the MYBPC3 gene was detected in this individual. This variant has been previously as disease-causing (PMID: 21488308, 24113344, 23549607; 26914223). Studies characterizing the effect of the c.927-9G>A variant on MYBPC3 function have shown splicing at exon 11 is absent and protein levels are reduced (PMID: 25031304). Therefore, this variant is classified as a pathogenic variant in accordance with ACMG guidelines. -
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Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with hypertrophic cardiomyopathy 4 (HCM; MIM#115197). (I) 0108 - This gene is associated with both recessive and dominant disease. Dominant inheritance is frequently reported in adult onset conditions, however recessive inheritance results in a more severe early onset phenotype (OMIM). (I) 0115 - Variants in this gene are known to have variable expressivity (PMID: 32841044). (I) 0209 - Splice site variant proven to affect splicing of the transcript with uncertain effect on protein sequence. Minigene assay in HeLa cells demonstrated out-of-frame skipping of exon 12, which is predicted to cause a frameshift and result in nonsense-mediated decay (NMD) (Crehalet, H. et al. (2012)). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v3) <0.01 (2 heterozygotes, 0 homozygotes). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified primarily as pathogenic by multiple clinical diagnostic laboratories (ClinVar). Additionally, this variant has been reported as pathogenic in eight HCM probands or families by VCGS. (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Hypertrophic cardiomyopathy Pathogenic:4
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This sequence change falls in intron 11 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. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has been observed in individuals with hypertrophic cardiomyopathy (PMID: 23549607, 24113344, 24810389, 26914223, 28615295, 29030401, 29121657). It has also been observed to segregate with disease in related individuals. This variant is also known as IVS11-9G>A. ClinVar contains an entry for this variant (Variation ID: 42807). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in inclusion of intron 11, and produces a non-functional protein and/or introduces a premature termination codon (PMID: 25031304). For these reasons, this variant has been classified as Pathogenic. -
The c.927-9G>A variant in MYBPC3 has been reported in >20 individuals with hypertrophic cardiomyopathy (HCM) and segregated with disease in at least 8 affected individuals from 7 families (Rodriguez-Garcia 2010 PMID: 21488307, Rodriguez-Garcia 2010 PMID: 20433692, Crehalet 2012, Das 2014 PMID: 24113344, Murphy 2016 PMID: 26914223, Viswanathan 2017 PMID: 29121657, Marschall 2019 PMID: 31737537, O'Leary 2019 PMID: 30550750, LMM data). It has also been reported by multiple clinical laboratories in ClinVar (Variation ID 42807) and has been identified in 0.001% (1/95618) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant occurs in the conserved splice consensus sequence and in vitro splicing studies suggest that it disrupts splicing, leading to an abnormal or absent protein (Crehalet 2012, Helms 2014 PMID: 25031304). In summary, the c.927-9G>A variant meets criteria to be classified as pathogenic for autosomal dominant HCM. ACMG/AMP criteria applied: PS4, PP1_Strong, PS3_Moderate, PM2_Supporting. -
The c.927-9G>A variant, located in the splice region of intron 11 of the MYBPC3 gene (also known as IVS11-9G>A in literature), is predicted to impact splicing (SpliceAI delta score: 0.29). A mini-gene splicing assay exhibited the existence of a short transcript lacking exon 12 in approximately equal amount of the normal transcript in wild type Hela cells (Crehalet 2012, doi.org/10.4081/cardiogenetics.2012.e6). This study has also shown that this variant causes complete skipping of exon 12, which is expected to result in frameshift and premature translation stop. Another study using ventricular myocardial tissue from an individual affected with hypertrophic cardiomyopathy (HCM) has shown that this variant causes inclusion of intron 11 and premature truncation in ~40% of the transcripts (PMID: 25031304). A recent study using RNA samples from two affected carriers could only detect band responding to WT with intensity reduced or disappear (PMID: 30645170), which may account for the 35% reduction in MyBP-C in the individual HCM sample with variant c.927-9G>A (PMID: 30550750). This variant has been reported in over 20 individuals affected with HCM (PMID: 21488308, 20433692, 23549607, 24113344, 26914223, 29121657, 31737537, 30550750, 28408708, 28615295, 28790153, 29030401, 33658374, 35508642). This variant has been observed to segregate with HCM in multiple families (PMID: 20433692, 24113344, 33658374). In addition, this variant has been identified in 2/217270 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on these evidence, the c.927-9G>A variant in MYBPC3 is classified as pathogenic.[Bo, 2024-03-18] -
Cardiomyopathy Pathogenic:2
This variant is located in intron 11 of the MYBPC3 gene (also known as IVS11-9G>A in literature). A mini-gene splicing assay has shown that the wild type construct results in approximately equal amounts of the normal transcript and the short transcript lacking exon 12, suggesting that the weak acceptor site of intron 11 was not always recognized (Crehalet 2012, doi.org/10.4081/cardiogenetics.2012.e6). This study has also shown that this variant causes complete skipping of exon 12, which is expected to result in frameshift and premature translation stop. In a study using ventricular myocardial tissue from an individual affected with hypertrophic cardiomyopathy, this variant has been shown to cause inclusion of intron 11 and premature truncation in ~40% of the transcripts (PMID: 25031304). A recent study using RNA samples from two affected carriers did not detect aberrant splicing, although the possibility of RNA degradation cannot be ruled out (PMID: 30645170). This variant has been reported in over 20 individuals affected with hypertrophic cardiomyopathy (PMID: 20433692, 23549607, 24113344, 26914223, 28408708, 28615295, 28790153, 29030401, 33658374, 35508642). This variant has also been reported to segregate with hypertrophic cardiomyopathy in multiple families (PMID: 20433692, 24113344; communication with external laboratory, ClinVar SCV000059334.6). This variant has been identified in 2/217270 chromosomes in the general population by the Genome Aggregation Database (gnomAD). 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.927-9G>A alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing, however at least one publication reports experimental evidence that this variant affects mRNA splicing, resulting in skipping of exon 12 (e.g. Crehalet_2012). The variant allele was found at a frequency of 5.4e-06 in 186306 control chromosomes. c.927-9G>A has been reported in the literature in multiple individuals affected with Hypertrophic Cardiomyopathy (e.g. Rodriguez-Garcia_2010, Crehalet_2012, Das_2014), and co-segregated with disease in multiple families (Rodriguez-Garcia_2010, Das_2014). These data indicate that the variant is very likely to be associated with disease. 11 other ClinVar submitters (evaluation after 2014) have cited the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Hypertrophic cardiomyopathy 4;C3715165:Left ventricular noncompaction 10 Pathogenic:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at