Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| LDLR- |
RCV000238298 | SCV000294500 | likely pathogenic | Hypercholesterolemia, familial, 1 | 2016-03-25 | criteria provided, single submitter | literature only | |
| Invitae | RCV001854884 | SCV002236215 | pathogenic | Familial hypercholesterolemia | 2023-09-26 | criteria provided, single submitter | clinical testing | Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This sequence change affects a donor splice site in intron 2 of the LDLR 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 LDLR are known to be pathogenic (PMID: 20809525, 28645073). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individuals with familial hypercholesterolemia (PMID: 10441197, 20145306). This variant is also known as IVS2+1G>A. ClinVar contains an entry for this variant (Variation ID: 251048). For these reasons, this variant has been classified as Pathogenic. |
| Ambry Genetics | RCV002411079 | SCV002723634 | pathogenic | Cardiovascular phenotype | 2023-03-03 | criteria provided, single submitter | clinical testing | The c.190+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon two of the LDLR gene. This alteration, also referred to as IVS2+1G>A, has been detected in familial hypercholesterolemia cohorts (Peeters AV et al. Mol. Cell. Probes, 1999 Aug;13:257-60; Chmara M et al. J. Appl. Genet., 2010;51:95-106). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. 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. |