rs397515916
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PP3PP5_Very_Strong
The NM_000256.3(MYBPC3):c.1624+4A>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000372 in 1,584,178 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Consequence
NM_000256.3 splice_region, intron
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Likely_pathogenic. Variant got 9 ACMG points.
Transcripts
RefSeq
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| MYBPC3 | ENST00000545968.6 | c.1624+4A>T | splice_region_variant, intron_variant | Intron 17 of 34 | 5 | NM_000256.3 | ENSP00000442795.1 | |||
| MYBPC3 | ENST00000399249.6 | c.1624+4A>T | splice_region_variant, intron_variant | Intron 16 of 33 | 5 | ENSP00000382193.2 | ||||
| MYBPC3 | ENST00000544791.1 | n.1624+4A>T | splice_region_variant, intron_variant | Intron 17 of 26 | 5 | ENSP00000444259.1 |
Frequencies
GnomAD3 genomes 0.0000263 AC: 4AN: 152102Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000133 AC: 3AN: 224880Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 121328
GnomAD4 exome AF: 0.0000384 AC: 55AN: 1432076Hom.: 0 Cov.: 31 AF XY: 0.0000296 AC XY: 21AN XY: 708990
GnomAD4 genome 0.0000263 AC: 4AN: 152102Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2AN XY: 74308
ClinVar
Submissions by phenotype
not provided Pathogenic:5Other:1
- -
- -
Published functional studies demonstrate that c.1624+4 A>T results in skipping of exon 17 (Helms et al., 2014; Singer et al., 2019); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 31028938, 23396983, 23782526, 19574547, 22563033, 21415409, 22057632, 27688314, 16199542, 28679633, 30645170, 22267749, 28615295, 28790153, 31099476, 31447099, 32123317, 33673806, 31006259, 30550750, 34135346, 33190526, 32079122, 25031304, Wood_2021_Article) -
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 IVS17+4A>T Based on the data reviewed below we consider it likely disease causing. The variant has been seen in at least 10 and as many as 13 unrelated cases of HCM. There is no segregation data. Ingles et al (2005) reported the variant 1 of 80 individuals with HCM in their Australian cohort (variant referred to as IVS18+4A>T). Kaski et al (2009) reported the variant in 1 of 79 pediatric cases of HCM from their British cohort (variant referred to as IVS18+4A>T). The same group reported what appears to be the same variant (referred to as intron17 DS A>T+4) in a 42yo male with HCM and a family history of sudden death and HCM (Marston et al 2009). They note they studied two additional patients with this variant but do not provide clinical details. The same group later reported IVS17+4>T in three affected individuals (Page et al 2012), which presumably overlap with the cases studied in Marston et al (2009). It is unclear whether these overlap with the pediatric case initially reported by this group (Kaski et al 2009) or whether these three individuals are related to one another. Maron et al (2012) reported the variant in a patient labeled as "genotype positive-phenotype negative" who had myocardial crypts on MRI. Two different splicing algorithms predict the variant to alter splicing. Thus it is expected to lead to no protein product due to nonsense mediated decay or to a truncated protein product. Marston et al (2009) studied myectomy samples from three individuals with this variant. They did not detect a truncated protein product but they did see in all three cases that the amount of protein was significantly decreased compared to heart tissue samples from hearts without HCM (donor hearts) and HCM patients without MYBPC3 variants. Splicing and other protein-truncating variants in MYBPC3 are a frequent cause of HCM (Erdmann et al. 2001 & 2003; Stenson et al 2003; Harvard Sarcomere Protein Gene Mutation Database). 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 (Harvard Sarcomere Protein Gene Mutation Database). In total the variant has not been seen in ~6950 published controls and individuals from publicly available population datasets. The variant is not listed in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~6200 Caucasian and African American individuals (as of February 12th, 2013). The variant is not listed in dbSNP or 1000 genomes. The variant was not observed in the following published and laboratory control samples: 200 presumed healthy individuals analyzed at GeneDx, over 400 presumed healthy individuals analyzed at Transgenomic, 150 healthy adults studied by Ingles et al (2005). -
GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -
- -
Hypertrophic cardiomyopathy Pathogenic:4
This sequence change falls in intron 17 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 present in population databases (rs397515916, gnomAD 0.007%). This variant has been observed in individuals with hypertrophic cardiomyopathy (PMID: 16199542, 19574547, 23782526, 28790153). This variant is also known as IVS18+4A>T or intron17 DS A>T+4. ClinVar contains an entry for this variant (Variation ID: 42556). 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 skipping of exon 17, 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.1624+4A>T variant in MYBPC3 has been identified in >15 individuals with HCM and segregated with disease in 5 affected family members from 3 families (Ingles 2005, Marston 2009, Helms 2014, Burns 2017, Springer 2019, Cardiogenomics pers comm, LMM data). This variant also been identified in 3/224880 chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant is located in the 5' splice region multiple studies have demonstrated that it causes skipping of exon 17, leading to the introduction of a premature stop codon (Helms 2014, Ito 2017, Springer 2019). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant HCM. ACMG/AMP Criteria applied: PS3, PS4, PM2, PP1_Moderate. -
- -
The c.1624+4A>T intronic variant of the MYBPC3 gene has been reported in multiple individuals affected with hypertrophic cardiomyopathy (PMID: 16199542, 19574547, 20031618, 22267749, 28790153, 23782526, 27688314, 30645170). RNA analysis indicates that this variant induces altered splicing due to donor loss. Variants that disrupt the donor or acceptor splice site typically leads to a loss of protein function (PMID: 16199547). Loss-of-function variants in MYBPC3 are known to be pathogenic (PMID: 19574547). This variant is also known as IVS18+4A>T. Functional studies with peripheral blood, septal myectomy and transplant specimens have shown that this variant disrupts mRNA splicing, resulting in skipping of exon 17 and introduction of a premature translation stop codon (PMID: 25031304, 30645170). This variant has been identified in 3/224880 chromosomes in the general population by gnomAD database. Based on the available evidence, the c.1624+4A>T intronic variant in MYBPC3 gene is classified as pathogenic. -
Hypertrophic cardiomyopathy 4 Pathogenic:3
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) 0210 - Splice site variant proven to affect splicing of the transcript with a known effect on protein sequence. RT-PCR on patient RNA demonstrated that this variant results in the skipping of exon 17, and subsequently the production of a premature termination codon. This new protein consequence (p.(Trp486*)) is predicted to undergo nonsense-mediated decay (PMID: 25031304). (SP) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v3) <0.001 for a dominant condition (4 heterozygotes, 0 homozygotes). (SP) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. These variants have been reported as pathogenic in many individuals with HCM (Decipher, PMID: 28771489). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported as pathogenic in multiple individuals with HCM (ClinVar, PMID: 28790153, 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 -
• The c.1624+4A>T variant in the MYBPC3 gene has been previously reported in the literature in at least 13 unrelated individuals with hypertrophic cardiomyopathy (Ingles et al., 2005; Marston et al., 2009; Helms et al., 2014; Burns et al., 2017; Singer et al., 2019; O’Hare et al., 2020), and has been reported by clinical labs to be detected in individuals undergoing testing for hypertrophic cardiomyopathy (ClinVar). • This variant has been identified in 3/224,880 chromosomes by the Genome Aggregation Database (http://gnomad.broadinstitute.org/). Although this variant has been seen in the general population, its frequency is low enough to be consistent with the prevalence of hypertrophic cardiomyopathy. • This variant alters the donor splice site in intron 17, which is predicted to result in abnormal gene splicing. Functional studies have demonstrated that this variant results in skipping of exon 17 (Helms et al., 2014; Singer et al., 2019). • These data were assessed using the ACMG/AMP variant interpretation guidelines. In summary, there is sufficient evidence to classify the c.1624+4A>T variant as pathogenic for autosomal dominant MYBPC3- related cardiomyopathy based on the information above. [ACMG evidence codes used: PS4; PS3; PM2; PP3] -
- -
Cardiomyopathy Pathogenic:2
This variant replaces the conserved c.A nucleotide with c.T at c.1624+4 position in intron 17 splice donor site of the MYBPC3 gene. Functional RNA studies have shown that this variant causes skipping of exon 17, frameshift and premature truncation, resulting in a truncated or absent protein product (PMID: 25031304, 30645170). This variant has been reported in over ten individuals affected with hypertrophic cardiomyopathy (PMID: 16199542, 19574547, 23782526, 28408708, 28615295, 28790153, 30645170). This variant has been identified in 3/224880 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of MYBPC3 function is a known mechanism of disease. Based on the available evidence, this variant is classified as Pathogenic. -
- -
Left ventricular noncompaction 10 Pathogenic:1
- -
Primary familial hypertrophic cardiomyopathy Pathogenic:1
Variant summary: The MYBPC3 c.1624+4A>T variant involves the alteration of a conserved intronic nucleotide. One in silico tool predicts a damaging outcome for this variant. 5/5 splice prediction tools predict the weakening or loss of a cannonical splice donor site, which has been confirmed by functional studies which show the variant to lead to exon 17 skipping and premature termination (Helms_2014). This variant was found in 3/223428 control chromosomes at a frequency of 0.0000134, which does not exceed the estimated maximal expected allele frequency of a pathogenic MYBPC3 variant (0.0010005).The variant has been reported in numerous affected individuals in the literature (Ingles_2005, Marston_2009, Page_2012, Nunez_2013, Helms_2016), and has been reported by clinical labs to be detected in individuals being tested for HCM (ClinVar). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. -
Cardiovascular phenotype Pathogenic:1
The c.1624+4A>T intronic pathogenic mutation results from an A to T substitution 4 nucleotides after coding exon 17 in the MYBPC3 gene. This alteration (also referred to as IVS17+4A>T) has been reported in multiple unrelated individuals with hypertrophic cardiomyopathy (HCM) and segregated with disease in three families tested by outside laboratories (Ingles J et al. J Med Genet. 2005;42(10):e59; Marston S et al. Circ Res. 2009;105(3):219-22; Núñez L et al. Circ J. 2013;77(9):2358-65; Burns C et al. Circ Cardiovasc Genet. 2017;10(4); external communication). Skipping of exon 17, which is predicted to lead to a frameshift, was detected on analysis of cardiac tissue from an affected carrier, and RNA analysis in blood samples from carriers identified by another group also confirmed skipping of exon 17 (Helms AS et al. Circ Cardiovasc Genet. 2014;7(4):434-43; Singer ES et al. Circ Genom Precis Med. 2019;12(1):e002368). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -
MYBPC3-related disorder Pathogenic:1
The MYBPC3 c.1624+4A>T variant is predicted to interfere with splicing. This variant has been reported in multiple unrelated individuals with hypertrophic cardiomyopathy (Ingles et al. 2005. PubMed ID: 16199542, described as IVS18+4A>T; Marston et al. 2009. PubMed ID: 19574547, described as intron17 DS A>T+4; Page et al. 2012. PubMed ID: 22267749, described as IVS17+4A>T; Singer et al. 2019. PubMed ID: 30645170). Complementary DNA studies in myocardial samples showed that the c.1624+4A>T results in skipping of exon 17 (Helms et al. 2014. PubMed ID: 25031304; Singer et al. 2019. PubMed ID: 30645170). This variant is reported in 0.0067% of alleles in individuals of African descent in gnomAD. This variant is interpreted as pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at