Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| LDLR- |
RCV000237970 | SCV000294611 | likely pathogenic | Hypercholesterolemia, familial, 1 | 2016-03-25 | criteria provided, single submitter | literature only | |
| Color Diagnostics, |
RCV000775034 | SCV000909131 | likely pathogenic | Familial hypercholesterolemia | 2019-03-12 | criteria provided, single submitter | clinical testing | This variant is located in intron 3 of the LDLR gene and changes a highly conserved nucleotide near the splice donor site. Computational splicing tools suggest that this variant may have significant impact on the RNA splicing. A mini-gene splicing assay has shown that this variant mainly causes an in-frame skipping of exon 3 (PMID: 26802169). LDLR exon 3 encodes the second LDLR type A repeat of the ligand binding domain, and absence of this exon is likely to have deleterious impact on LDLR function. This variant has been reported to segregate with disease in a Moroccan family affected with familial hypercholesterolemia (PMID: 16806138). In this family, homozygous father was reported with a very high level of LDL-C and suffered cerebrovascular disease at age 30 and had coronary manifestation (two myocardial infraction and two coronary bypasses) at age 35. His three heterozygous children were reported to be affected with hypercholesterolemia. This variant has also been identified in an unrelated individual affected with hypercholesterolemia (PMID: 26802169). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). A different variant at the same position (c.313+5G>A) has been shown to cause exon 3 skipping and has been associated with familial hypercholesterolemia (PMID: 11317362, 17094996). Based on available evidence, this variant is classified as Likely Pathogenic. |
| Quest Diagnostics Nichols Institute San Juan Capistrano | RCV004999166 | SCV005625845 | likely pathogenic | not provided | 2024-07-25 | criteria provided, single submitter | clinical testing | The LDLR c.313+5G>T variant has been reported in the published literature in individuals with hypercholesterolemia including a family with a homozygous father and his three heterozygous children (PMIDs: 16806138 (2006) and 26802169 (2016)). Also, an experimental study using a minigene splicing assay showed that this variant results in exon 3 skipping (PMID: 26802169 (2016)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Analysis of this variant using software algorithms for the prediction of the effect of nucleotide changes on splicing yielded predictions that this variant may affect proper LDLR mRNA splicing. Based on the available information, this variant is classified as likely pathogenic. |
| Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, |
RCV000237970 | SCV000606079 | pathogenic | Hypercholesterolemia, familial, 1 | no assertion criteria provided | research |