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 | |
| Invitae | RCV002518497 | SCV003216242 | pathogenic | Familial hypercholesterolemia | 2022-02-02 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. Studies have shown that this variant is associated with altered splicing, but the impact on the resulting protein product is unknown (PMID: 7545204). Studies have shown that disruption of this splice site alters LDLR gene expression (PMID: 7545204). ClinVar contains an entry for this variant (Variation ID: 252272). Disruption of this splice site has been observed in individuals with familial hypercholesterolemia (PMID: 7545204, 16389549). This variant is not present in population databases (gnomAD no frequency). 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). |
| Ambry Genetics | RCV003298319 | SCV004000132 | pathogenic | Cardiovascular phenotype | 2023-05-30 | criteria provided, single submitter | clinical testing | The c.2311+1G>A intronic pathogenic mutation 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 cause aberrant splicing. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. 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 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 N et al. J Lipid Res, 1995 Jun;36:1315-24; Bertolini S et al. Arterioscler Thromb Vasc Biol, 1999 Feb;19:408-18Di Taranto MD et al. Clin Genet, 2021 Nov;100:529-541). This variant has been reported to result in aberrant splicing (Lelli N et al. J Lipid Res, 1995 Jun;36:1315-24). 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. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. |