Total submissions: 6
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Laboratory for Molecular Medicine, |
RCV000204012 | SCV000059317 | pathogenic | Hypertrophic cardiomyopathy | 2011-06-10 | criteria provided, single submitter | clinical testing | The 772+1G>A variant has been identified in four HCM probands (2 cases in Erdman 2001 - reported as IVS7+1G>A and 2 cases in our laboratory). One of these proba nds had a family history of HCM and the variant segregated with disease in three additional affected family members. This variant alters the highly conserved -1 splicing position, and has been shown to result in the skipping of exon 7 or ex ons 7 and 8, both of which cause a frame shift and a premature termination signa l (Erdmann 2001). In summary, this data meets our criteria to classify this vari ant as pathogenic. |
Invitae | RCV000204012 | SCV000261645 | pathogenic | Hypertrophic cardiomyopathy | 2023-11-01 | criteria provided, single submitter | clinical testing | This sequence change affects a donor splice site in intron 6 of the MYBPC3 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product. This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 11499719). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 42790). Studies have shown that disruption of this splice site results in skipping of exon 6 and exons 6 and 7 and introduces a premature termination codon (PMID: 11499719). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. |
Ambry Genetics | RCV000250001 | SCV000318796 | pathogenic | Cardiovascular phenotype | 2022-07-27 | criteria provided, single submitter | clinical testing | The c.772+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 6 of the MYBPC3 gene. This alteration (also referred to as IVS7+1G>A) has been reported in subjects with hypertrophic cardiomyopathy (HCM) and was shown to segregate with disease in one family (Erdmann J et al. J. Am. Coll. Cardiol., 2001 Aug;38:322-30; Alfares AA et al. Genet. Med., 2015 Nov;17:880-8; Walsh R et al. Genet. Med., 2017 02;19:192-203). This alteration has also been reported to impact mRNA splicing (Erdmann J et al. J. Am. Coll. Cardiol., 2001 Aug;38:322-30). 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, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as a disease-causing mutation. |
ARUP Laboratories, |
RCV001781348 | SCV001470942 | pathogenic | not provided | 2019-11-11 | criteria provided, single submitter | clinical testing | The MYBPC3 c.772+1G>A variant (rs397516072), also published as IVS7+1G>A, is reported in the literature in multiple individuals affected with hypertrophic cardiomyopathy (Erdmann 2001, Walsh 2017). In one family, this variant was observed to segregate with disease in all affected members (Erdmann 2001). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. This variant abolishes the canonical splice donor site of intron 6, which is likely to disrupt gene function. Indeed, RNA analyses of individuals with this variant exhibit skipping of exon 6 or exons 6 and 7 (Erdmann 2001). Based on available information, this variant is considered to be pathogenic. References: Erdmann J et al. Spectrum of clinical phenotypes and gene variants in cardiac myosin-binding protein C mutation carriers with hypertrophic cardiomyopathy. J Am Coll Cardiol. 2001 Aug;38(2):322-30. Walsh R et al. Reassessment of Mendelian gene pathogenicity using 7,855 cardiomyopathy cases and 60,706 reference samples. Genet Med. 2017 Feb;19(2):192-203. |
Revvity Omics, |
RCV001781348 | SCV002017655 | pathogenic | not provided | 2019-10-09 | criteria provided, single submitter | clinical testing | |
CHEO Genetics Diagnostic Laboratory, |
RCV003486552 | SCV004239392 | pathogenic | Cardiomyopathy | 2022-10-03 | criteria provided, single submitter | clinical testing |