Total submissions: 7
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Laboratory for Molecular Medicine, |
RCV000533067 | SCV000059215 | pathogenic | Hypertrophic cardiomyopathy | 2016-05-16 | criteria provided, single submitter | clinical testing | The p.Trp1078X variant in MYBPC3 has been identified by our laboratory in 4 indi viduals with HCM. It has also been identified in 1/23606 European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP r s397516006). This nonsense variant leads to a premature termination codon at pos ition 1078, which is predicted to lead to a truncated or absent protein. Heteroz ygous loss of function of the MYBPC3 gene is an established disease mechanism in individuals with HCM. In summary, the p.Trp1078X variant meets our criteria to be classified as pathogenic for HCM in an autosomal dominant manner based upon i ts predicted impact to the protein. |
| Labcorp Genetics |
RCV000533067 | SCV000623587 | pathogenic | Hypertrophic cardiomyopathy | 2024-08-20 | criteria provided, single submitter | clinical testing | This sequence change creates a premature translational stop signal (p.Trp1078*) 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). 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 premature translational stop signal has been observed in individuals with hypertrophic cardiomyopathy (PMID: 19574547, 25031304). ClinVar contains an entry for this variant (Variation ID: 42692). For these reasons, this variant has been classified as Pathogenic. |
| Centre for Mendelian Genomics, |
RCV001198904 | SCV001369899 | pathogenic | Hypertrophic cardiomyopathy 4 | 2018-11-06 | criteria provided, single submitter | clinical testing | This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PP3,PP5. |
| CHEO Genetics Diagnostic Laboratory, |
RCV001798086 | SCV002042197 | pathogenic | Cardiomyopathy | 2023-03-01 | criteria provided, single submitter | clinical testing | |
| Ambry Genetics | RCV002444468 | SCV002611736 | pathogenic | Cardiovascular phenotype | 2024-07-25 | criteria provided, single submitter | clinical testing | The p.W1078* pathogenic mutation (also known as c.3233G>A), located in coding exon 30 of the MYBPC3 gene, results from a G to A substitution at nucleotide position 3233. This changes the amino acid from a tryptophan to a stop codon within coding exon 30. This variant has been detected in individuals with features consistent with hypertrophic cardiomyopathy (Helms AS et al. Circ Cardiovasc Genet, 2014 Aug;7:434-43; Helms AS et al. Circulation, 2016 Nov;134:1738-1748; Walsh R et al. Genet. Med., 2017 Feb;19:192-203). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. |
| Gene |
RCV003226900 | SCV003923348 | pathogenic | not provided | 2024-01-17 | criteria provided, single submitter | clinical testing | Reported in association with HCM in a patient referred for genetic testing at GeneDx and in the published literature (PMID: 27532257, 25031304); Not observed at significant frequency in large population cohorts (gnomAD); Nonsense 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; This variant is associated with the following publications: (PMID: 25031304, 27532257, 19574547, 27688314) |
| Juno Genomics, |
RCV001198904 | SCV005871439 | pathogenic | Hypertrophic cardiomyopathy 4 | criteria provided, single submitter | clinical testing | PM2_Supporting+PVS1+PS4 |