Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| LDLR- |
RCV000237904 | SCV000295940 | pathogenic | Hypercholesterolemia, familial, 1 | 2016-03-25 | criteria provided, single submitter | literature only | |
| Cardiovascular Research Group, |
RCV000237904 | SCV000599408 | pathogenic | Hypercholesterolemia, familial, 1 | 2016-03-01 | criteria provided, single submitter | curation | |
| Laboratory of molecular diagnosis of dyslipidemias, |
RCV000237904 | SCV001653658 | pathogenic | Hypercholesterolemia, familial, 1 | 2021-05-24 | criteria provided, single submitter | clinical testing | |
| Labcorp Genetics |
RCV002518497 | SCV003216242 | pathogenic | Familial hypercholesterolemia | 2024-07-16 | criteria provided, single submitter | clinical testing | This sequence change affects a donor splice site in intron 15 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: 7545204, 16389549). ClinVar contains an entry for this variant (Variation ID: 252272). Studies have shown that disruption of this splice site alters LDLR gene expression (PMID: 7545204). 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. |
| Ambry Genetics | RCV003298319 | SCV004000132 | pathogenic | Cardiovascular phenotype | 2023-09-18 | criteria provided, single submitter | clinical testing | The c.2311+1G>A intronic variant results from a G to A substitution one nucleotide after coding exon 15 of the LDLR gene. Alterations that disrupt the canonical splice site are expected to result in aberrant splicing. The resulting transcript is predicted to be in-frame and is not expected to trigger nonsense-mediated mRNAdecay; however, direct evidence is unavailable. The exact functional effect of the altered amino acid sequence is unknown; however, a significant portion of the protein is affected and the impacted region is critical for protein function (Ambry internal data). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant has been reported in the homozygous state in a proband with clinical features consistent with homozygous familial hypercholesterolemia with demonstrated reduced LDLR activity in fibroblasts, and has also been detected in the heterozygous state in individuals with hypercholesterolemia(Lelli, 1995; Bertolini, 1999; Di Taranto, 2021). This nucleotide position is highly conserved in available vertebrate species. Functional studies found that the c.2311+1G>A variant activated two cryptic donor splice sites that led to skipping of exon 15. The overall amount of LDLR in the proband’s fibroblasts was found to be 10% of that in controls (Lelli, 1995). In silico splice site analysis predicts that this alteration will weaken the native splice donor site. Based on the available evidence, this alteration is classified as pathogenic. |