Total submissions: 9
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Women's Health and Genetics/Laboratory Corporation of America, |
RCV000030293 | SCV000052960 | pathogenic | Primary familial hypertrophic cardiomyopathy | 2019-01-17 | criteria provided, single submitter | clinical testing | Variant summary: MYBPC3 c.932C>A (p.Ser311X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant was absent in 203230 control chromosomes (gnomAD). c.932C>A has been reported in the literature in individuals affected with Hypertrophic Cardiomyopathy (Waldmuller 2008, Berge 2013, Nannenberg 2011, Walsh 2017). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three ClinVar submissions from other clinical diagnostic laboratories (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. |
Laboratory for Molecular Medicine, |
RCV000844687 | SCV000198940 | pathogenic | Hypertrophic cardiomyopathy | 2015-01-14 | criteria provided, single submitter | clinical testing | The p.Ser311X variant in MYBPC3 has been reported in 4 individuals with HCM (Wal dmuller 2008, Nannenberg 2011, Hoedemaekers 2011- in: Michels 2011, doctoral the sis) and was absent from large population studies. This variant has also been id entified by our laboratory in 1 Caucasian individual with HCM. This nonsense var iant leads to a premature termination codon at position 311, which is predicted to lead to a truncated or absent protein. Heterozygous loss-of-function of the M YBPC3 gene is an established disease mechanism in individuals with HCM. In summa ry, this variant meets our criteria to be classified as pathogenic (http://pcpgm .partners.org/LMM) based on the predicted impact of the variant. |
Gene |
RCV000158304 | SCV000208239 | pathogenic | not provided | 2020-11-10 | criteria provided, single submitter | clinical testing | Reported in assocation with HCM and one patient with DCM; one patient with childhood onset HCM harbored another variant in the MYBPC3 gene (Waldmller et al., 2008; Berge et al., 2014; Walsh et al., 2017; van Waning et al., 2018); Not observed in large population cohorts (Lek et al., 2016); 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; Reported in ClinVar as pathogenic (ClinVar Variant ID# 36615; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 29447731, 27532257, 20019025, 18258667, 24111713, 22115648) |
Clinical Genetics DNA and cytogenetics Diagnostics Lab, |
RCV000603903 | SCV000744859 | pathogenic | Hypertrophic cardiomyopathy 4 | 2015-09-21 | criteria provided, single submitter | clinical testing | |
Invitae | RCV000844687 | SCV001584172 | pathogenic | Hypertrophic cardiomyopathy | 2023-11-05 | criteria provided, single submitter | clinical testing | This sequence change creates a premature translational stop signal (p.Ser311*) 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 MYBPC3-related conditions (PMID: 18258667, 22115648, 27532257, 29447731). ClinVar contains an entry for this variant (Variation ID: 36615). For these reasons, this variant has been classified as Pathogenic. |
Ambry Genetics | RCV002371794 | SCV002684866 | pathogenic | Cardiovascular phenotype | 2022-11-03 | criteria provided, single submitter | clinical testing | The p.S311* pathogenic mutation (also known as c.932C>A), located in coding exon 12 of the MYBPC3 gene, results from a C to A substitution at nucleotide position 932. This changes the amino acid from a serine to a stop codon within coding exon 12. This alteration has been reported in association with hypertrophic cardiomyopathy (HCM) (Waldmüller S et al. Clin. Chem., 2008 Apr;54:682-7; Nannenberg EA et al. J. Am. Coll. Cardiol., 2011 Nov;58:2406-14; Walsh R et al. Genet. Med., 2017 02;19:192-203; van Waning JI et al. J. Am. Coll. Cardiol., 2018 Feb;71:711-722). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition to the clinical data presented in the literature, 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. |
Diagnostic Laboratory, |
RCV000603903 | SCV000733057 | pathogenic | Hypertrophic cardiomyopathy 4 | no assertion criteria provided | clinical testing | ||
Genome Diagnostics Laboratory, |
RCV000158304 | SCV001932751 | pathogenic | not provided | no assertion criteria provided | clinical testing | ||
Clinical Genetics, |
RCV000158304 | SCV001978826 | pathogenic | not provided | no assertion criteria provided | clinical testing |