Total submissions: 8
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Invitae | RCV000465441 | SCV000546468 | pathogenic | Hypertrophic cardiomyopathy | 2024-01-08 | criteria provided, single submitter | clinical testing | This sequence change affects an acceptor splice site in intron 22 of the MYBPC3 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in MYBPC3 are known to be pathogenic (PMID: 19574547). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individuals with hypertrophic cardiomyopathy (PMID: 23782526). ClinVar contains an entry for this variant (Variation ID: 177814). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. |
ARUP Laboratories, |
RCV000506011 | SCV000604328 | pathogenic | not specified | 2016-11-16 | criteria provided, single submitter | clinical testing | |
Gene |
RCV000786163 | SCV001831981 | pathogenic | not provided | 2020-12-08 | criteria provided, single submitter | clinical testing | Not observed in large population cohorts (Lek et al., 2016); Canonical splice site variant in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 23782526, 30393631, 27532257) |
Revvity Omics, |
RCV000786163 | SCV002017656 | pathogenic | not provided | 2021-08-31 | criteria provided, single submitter | clinical testing | |
Women's Health and Genetics/Laboratory Corporation of America, |
RCV002281967 | SCV002570549 | pathogenic | Primary familial hypertrophic cardiomyopathy | 2022-07-22 | criteria provided, single submitter | clinical testing | Variant summary: MYBPC3 c.2149-1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 3 acceptor site. Experimental evidence supports these predictions indicating that this variant affects mRNA splicing (Mendez_2021). The variant was absent in 237380 control chromosomes (gnomAD). c.2149-1G>A has been reported in the literature in multiple individuals affected with Hypertrophic Cardiomyopathy (e.g. Nunez_2013, Restrepo-Cordoba_2017, Mendez_2021). These data indicate that the variant is very likely to be associated with disease. Five ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. |
Ambry Genetics | RCV002426737 | SCV002730417 | pathogenic | Cardiovascular phenotype | 2021-12-18 | criteria provided, single submitter | clinical testing | The c.2149-1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide upstream from coding exon 23 of the MYBPC3 gene. This alteration was first reported in a hypertrophic cardiomyopathy (HCM) cohort (Núñez L et al. Circ. J., 2013 Jun;77:2358-65) and has also been reported in another HCM clinical genetic testing cohort; however, clinical details were limited (Walsh R et al. Genet. Med., 2017 Feb;19:192-203). 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. |
Laboratory for Molecular Medicine, |
RCV000465441 | SCV000204115 | pathogenic | Hypertrophic cardiomyopathy | 2013-03-04 | no assertion criteria provided | clinical testing | proposed classification - variant undergoing re-assessment, contact laboratory |
Stanford Center for Inherited Cardiovascular Disease, |
RCV000786163 | SCV000924854 | pathogenic | not provided | 2016-10-14 | no assertion criteria provided | provider interpretation | c.2149-1G>A (Splice acceptor IVS 22-1G>A) in the MYBPC3 gene (NM_000256.3) We have seen this variant in a person with HCM. Testing was performed by Invitae. The variant type is a well established mechanism of disease in this gene and we consider this variant to be very likely pathogenic and we do feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). This variant has been seen in at least 2 patients with HCM (not including this patient), representing weak case data. No segregation data is available. One LMM HCM patient is listed in the cardiodb site. Another HCM patient was reported in a Spanish cohort by Nunez, et al.,2013. Per the Invitae report, "This sequence change affects an acceptor splice site in intron 22 of the MYBPC3 gene. It is expected to disrupt mRNA splicing and likely results in an absent or disrupted protein product." There is no variation at genomic position (11-47360231-G-A) listed in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/), which currently includes variant calls on ~64,000 individuals of European, African, Latino and Asian descent (as of 10/14/2016). The mean coverage at that site in ExAC is ~22x, median is ~19x, and >90% of people have 10x coverage. |