Total submissions: 8
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Laboratory for Molecular Medicine, |
RCV000808027 | SCV000203961 | pathogenic | Hypertrophic cardiomyopathy | 2014-08-07 | criteria provided, single submitter | clinical testing | The Cys1124X variant in MYBPC3 has been reported in 1 individual with HCM (Van D riest 2004). This variant was absent from large population studies. This nonsens e variant leads to a premature termination codon at position 1124, which is pred icted to lead to a truncated or absent protein. Heterozygous loss of function of the MYBPC3 gene is an established disease mechanism in individuals with HCM. In summary, this variant meets our criteria to be classified as pathogenic (http:/ /pcpgm.partners.org/LMM) based on the predicted impact of the variant. |
| Gene |
RCV000413211 | SCV000490642 | pathogenic | not provided | 2017-11-30 | criteria provided, single submitter | clinical testing | The C1124X variant in the MYBPC3 gene has been reported in association with HCM (Van Driest et al., 2004;Bashyam et al., 2012). Bashyam et al. (2012) describe an Indian boy with HCM at 3-years-old, though hisheterozygous mother and sibling remained asymptomatic. The C1124X variant is predicted to cause loss of normalprotein function either by protein truncation or nonsense-mediated mRNA decay. Other downstream nonsense variantsin the MYBPC3 gene have been reported in the Human Gene Mutation Database in association with HCM (Stensonet al., 2014), indicating that loss of function is a known disease mechanism. Furthermore, this variant is not observedin large population cohorts (Lek et al., 2016). |
| Ambry Genetics | RCV000619606 | SCV000740242 | pathogenic | Cardiovascular phenotype | 2021-09-13 | criteria provided, single submitter | clinical testing | The p.C1124* pathogenic mutation (also known as c.3372C>A), located in coding exon 31 of the MYBPC3 gene, results from a C to A substitution at nucleotide position 3372. This changes the amino acid from a cysteine to a stop codon within coding exon 31. This alteration has been reported in patients with hypertrophic cardiomyopathy (Van Driest SL et al. J. Am. Coll. Cardiol., 2004 Nov;44:1903-10; Bashyam MD et al. Mol Cell Biochem, 2012 Jan;360:373-82; Ko C et al. Genet Med, 2018 01;20:69-75; O'Leary TS et al. J Mol Cell Cardiol, 2019 02;127:165-173). 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. |
| CHEO Genetics Diagnostic Laboratory, |
RCV000769308 | SCV000900686 | pathogenic | Cardiomyopathy | 2021-12-14 | criteria provided, single submitter | clinical testing | |
| Invitae | RCV000808027 | SCV000948111 | pathogenic | Hypertrophic cardiomyopathy | 2023-09-30 | criteria provided, single submitter | clinical testing | This sequence change creates a premature translational stop signal (p.Cys1124*) 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 variant has not been reported in the literature in individuals affected with MYBPC3-related conditions. ClinVar contains an entry for this variant (Variation ID: 177701). For these reasons, this variant has been classified as Pathogenic. |
| Lifecell International Pvt. |
RCV003226219 | SCV003922056 | pathogenic | Hypertrophic cardiomyopathy 4 | criteria provided, single submitter | clinical testing | A Heterozygous Nonsense variant c.3372C>A in Exon 31 of the MYBPC3 gene that results in the amino acid substitution p.Cys1124* was identified. The observed variant is novel in gnomAD exomes and genomes. The severity of the impact of this variant on the protein is high, based on the effect of the protein and REVEL score. Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individual tools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for an individual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood that the variant is disease-causing. ClinVar has also classified this variant as Pathogenic [Variation ID: 177701]. The observed variant has bene previously reported in patients affected with familial hypertrophic cardiomyopathy (Bashyam, Murali D et al., 2012). For these reasons, this variant has been classified as Pathogenic. | |
| Baylor Genetics | RCV003226219 | SCV004041420 | pathogenic | Hypertrophic cardiomyopathy 4 | 2023-03-14 | criteria provided, single submitter | clinical testing | |
| Baylor Genetics | RCV003333033 | SCV004041550 | pathogenic | Left ventricular noncompaction 10 | 2023-03-14 | criteria provided, single submitter | clinical testing |