Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Molecular Genetics Laboratory, |
RCV000454717 | SCV000540752 | pathogenic | Hypercholesterolemia, familial, 1 | 2016-11-05 | criteria provided, single submitter | clinical testing | Disrupt SDE motif. SDE bind structural Ca2+. |
| Labcorp Genetics |
RCV002230305 | SCV000544689 | pathogenic | Familial hypercholesterolemia | 2017-02-21 | criteria provided, single submitter | clinical testing | This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a LDLR-related disease. For these reasons, this variant has been classified as Pathogenic. At least two different substitutions within this deleted sequence (p.Gln228Gln and p.Cys231Gly) have been determined to be pathogenic (PMID: 8882879, 16250003, 17094996, 8664907). This suggests that several residues within this region are critical for LDLR protein function. Algorithms developed to predict the effect of sequence changes on mRNA splicing suggest that this variant may alter RNA splicing, but this prediction has not been confirmed by published transcriptional studies. This sequence change deletes 12 nucleotides from exon 4 of the LDLR mRNA (c.683_694delAGGAAAACTGCG). This leads to the deletion of 4 amino acid residues in the LDLR protein (p.Glu228_Cys231del) but otherwise preserves the integrity of the reading frame. |
| Ambry Genetics | RCV002365581 | SCV002664280 | likely pathogenic | Cardiovascular phenotype | 2018-02-28 | criteria provided, single submitter | clinical testing | The c.683_694del12 variant (also known as p.E228_C231del) is located in coding exon 4 of the LDLR gene. This variant results from an in-frame AGGAAAACTGCG deletion at nucleotide positions 683 to 694 at the end of exon 4. This results in the deletion of four amino acids between codons 228 and 231. This alteration has been reported in a cohort of subjects with familial hypercholesterolemia (Tichý L et al. Physiol Res, 2017 Apr;66:S47-S54). In addition, internal structural analysis indicates that this alteration both alters the conserved SDE triplet motif and disrupts a disulfide bond in the LDL type A repeat 5, which is important for ligand binding (Ambry internal data). Based on four different splice site prediction tools, this alteration is expected to create an in-frame alternate splice donor site at the new exon-intron boundary created by the deletion; however, experimental evidence is not currently available. Based on the majority of available evidence to date, this variant is likely to be pathogenic. |