Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Laboratory for Molecular Medicine, |
RCV000475909 | SCV000059281 | pathogenic | Hypertrophic cardiomyopathy | 2012-02-03 | criteria provided, single submitter | clinical testing | |
| Gene |
RCV000158414 | SCV000208349 | pathogenic | not provided | 2023-04-26 | criteria provided, single submitter | clinical testing | Expression studies in neonatal rat ventricular cardiomyocytes showed this variant caused significantly reduced levels of a truncated protein and failed to exhibit sarcomere incorporation when compared to wild-type protein (Glazier et al., 2018); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 27532257, 23396983, 21959974, 28640247, 25335496, 29875314) |
| Invitae | RCV000475909 | SCV000546475 | pathogenic | Hypertrophic cardiomyopathy | 2024-01-24 | criteria provided, single submitter | clinical testing | This sequence change creates a premature translational stop signal (p.Ile154Leufs*5) in the MYBPC3 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MYBPC3 are known to be pathogenic (PMID: 19574547). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 21959974, 23396983, 25335496). ClinVar contains an entry for this variant (Variation ID: 42755). For these reasons, this variant has been classified as Pathogenic. |
| Fulgent Genetics, |
RCV002482963 | SCV002775668 | pathogenic | Hypertrophic cardiomyopathy 4; Left ventricular noncompaction 10 | 2021-09-23 | criteria provided, single submitter | clinical testing | |
| Stanford Center for Inherited Cardiovascular Disease, |
RCV000158414 | SCV000280271 | likely pathogenic | not provided | 2014-12-22 | 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. p.Ile154LeufsX5 (c.459delC) in MYBPC3 Given the data reviewed below, we consider this variant to be likely disease causing. This variant has been seen in at least 2 presumably unrelated individuals with HCM.. This variant has been reported in one Indian male who was 44 years of age and who had a 24 mm septum (Bashyam et al 2011). In that cohort another patient with HCM had c.456delC as well as a missense variant in MYBPC3, p.Glu710Lys. The authors do not report whether these two variants are cis or trans or any segregation data on either variant. Note in this publication the variant is notated as c.456delC, while GeneDx and HGMD refer to it as c.459delC. Unfortunately Bashyam et al don't include protein nomenclature that might help clarify what they are seeing. I checked with GeneDx about the discrepancy and they noted that the deleted C occurs in a string of Cs. They name the variant assuming the first C is deleted while Bashyam et al seem to notate assuming the last C is deleted (ACCC[C]ATTG vs. A[C]CCCATTTG). Zimmerman et al (2010) list this variant in a supplemental table of pathogenic variants for which genotyping probes were added to their resequencing array for dilated cardiomyopathy. This is a methods paper published by the Laboratory for Molecular Medicine team at Harvard. This suggests that they had reason to suspect this variant was pathogenic (likely unpublished internal data from their clinical genetic testing experience). This is a frame-shifting variant that creates a premature stop codon 5 codons downstream of the variant. The variant is expected to either cause a truncated protein or a completely absent protein due to nonsense-mediated mRNA decay. Many other frameshift and null variants have been identified in MYBPC3 in association with cardiomyopathy (ex. p.Trp792fs, p.Pro794fs, p.Lys1065fs, p.Cys1202fs, p.Pro1208fs, p.Trp1098ter, p.Glu1096ter, p.Cys1124ter, p.Gln1233ter). Furthermore, these types of variants in MYBPC3 are not seen in individuals without cardiomyopathy; there are no frameshift variants listed in the NHLBI Exome Sequencing Project dataset, which includes variant calls on ~6000 Caucasian and African American individuals (as of 7/30/2012). In total the variant has not been seen in 6100 published controls and publicly available general population samples, though note that all (or nearly all) of these samples do not match the patient’s ancestry. Bashyam et al report that the variant was absent in 100 presumably healthy controls (ancestry is not noted). GeneDx did not report control data. The variant is not listed in dbSNP or 1000 genomes. Nor is it not currently listed in the NHLBI Exome Sequencing Project dataset, which includes variant calls on ~6,000 Caucasian and African American individuals (as of July 2012). |