ClinVar Miner

Submissions for variant NM_000256.3(MYBPC3):c.1624+4A>T (rs397515916)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000168451 SCV000059070 pathogenic Hypertrophic cardiomyopathy 2015-04-17 criteria provided, single submitter clinical testing The c.1624+4A>T variant in MYBPC3 has been identified in >10 individuals with HC M and segregated with disease in 5 affected family members from 3 families (Ingl es 2005, Marston 2009, Cardiogenomics, personal communication, LMM data). In one family tested by an outside laboratory, the variant appeared to not segregate i n one affected individual, though the disease in this individual is likely a phe nocopy explained by environmental factors (personal communication). This variant also been identified in 1/44466 European chromosomes by the Exome Aggregation C onsortium (ExAC,; dbSNP rs397515916). Please note that for diseases with clinical variability or reduced penetrance, pathogenic v ariants may be present at a low frequency in the general population. This varian t is located in the 5' splice region and cDNA analysis of a cardiac tissue sampl e from a HCM patient with the c.1624+4A>T variant indicates that this variant re sults in skipping of exon 17, leading to a premature stop codon at position 486 (Helms 2014). Splice and other variants resulting in a heterozygous loss of MYBP C3 function are strongly associated with HCM. In summary, this variant meets cri teria to be classified as pathogenic for HCM in an autosomal dominant manner bas ed upon segregation studies, low frequency in the general population, and functi onal evidence.
GeneDx RCV000158106 SCV000208041 pathogenic not provided 2018-07-19 criteria provided, single submitter clinical testing The c.1624+4 A>T pathogenic variant has been identified in the MYBPC3 gene. This variant has previously been reported in association with HCM (Ingles et al., 2005; Marston et al., 2009; Page et al., 2012; Nunez et al., 2013). Ingles et al. (2005) identified c.1624+4 A>T (reported as IVS18+4 A>T due to a different exon numbering convention) in one family with HCM. Marston et al. (2009) reported this variant in a 42 year-old male patient with HCM and a family history of sudden cardiac death in his mother. Nunez et al. (2013) identified c.1624+4 A>T in three individuals with HCM. Additionally, this variant has been observed in multiple unrelated individuals referred for HCM genetic testing at GeneDx. Splice prediction algorithms predict that c.1624+4 A>T destroys the splice donor site of intron 17, which is predicted to cause abnormal gene splicing. Consistent with this prediction, Helms et al. (2014) studied sarcomere transcript from septal myectomy and transplant patients and concluded that c.1624+4 A>T results in skipping of exon 17. The c.1624+4 A>T variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016).
Invitae RCV000168451 SCV000219148 likely pathogenic Hypertrophic cardiomyopathy 2018-12-10 criteria provided, single submitter clinical testing This sequence change falls in intron 17 of the MYBPC3 mRNA. It does not directly change the encoded amino acid sequence of the MYBPC3 protein. This variant is present in population databases (rs397515916, ExAC <0.01%). This sequence change has been reported in the literature in several individuals affected with hypertrophic cardiomyopathy (PMID: 16199542, 19574547, 28790153, 23782526). This variant is also known in the literature as IVS18+4A>T and intron17 DS A>T+4. ClinVar contains an entry for this variant (Variation ID: 42556). Algorithms developed to predict the effect of intronic changes on mRNA splicing suggest that this sequence change may alter mRNA splicing, and this was confirmed by an experimental study on the splicing effect which found that this variant leads to skipping of exon 17 and creates a premature termination codon that may result in a truncated or absent protein product (PMID: 25031304). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Ambry Genetics RCV000249084 SCV000320645 pathogenic Cardiovascular phenotype 2019-03-01 criteria provided, single submitter clinical testing Good segregation with disease (lod 1.5-3 = 5-9 meioses);Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation;Functionally-validated splicing mutation
Integrated Genetics/Laboratory Corporation of America RCV000211799 SCV000917817 pathogenic Primary familial hypertrophic cardiomyopathy 2018-01-02 criteria provided, single submitter clinical testing 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.
Blueprint Genetics RCV000158106 SCV000927910 pathogenic not provided 2018-09-03 criteria provided, single submitter clinical testing
Stanford Center for Inherited Cardiovascular Disease, Stanford University RCV000158106 SCV000280218 likely pathogenic not provided 2015-06-19 no assertion criteria provided clinical testing 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, ClinGen RCV000158106 SCV000784698 not provided not provided no assertion provided phenotyping only 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.

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