Total submissions: 3
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
LDLR- |
RCV000237612 | SCV000295839 | likely pathogenic | Hypercholesterolemia, familial, 1 | 2016-03-25 | criteria provided, single submitter | literature only | |
Ambry Genetics | RCV002418066 | SCV002726488 | uncertain significance | Cardiovascular phenotype | 2021-02-02 | criteria provided, single submitter | clinical testing | The p.L682P variant (also known as c.2045T>C), located in coding exon 14 of the LDLR gene, results from a T to C substitution at nucleotide position 2045. The leucine at codon 682 is replaced by proline, an amino acid with similar properties. One functional study found impaired transport and reduced enzymatic activity of LDLR protein in a cell line bearing this alteration, however there was an additional unknown LDLR variant in the cell line, and details were limited (Hobbs HH et al. Hum Mutat, 1992;1:445-66). This nucleotide position is highly conserved in available vertebrate species. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
Invitae | RCV003581639 | SCV004297876 | likely pathogenic | Familial hypercholesterolemia | 2023-02-22 | criteria provided, single submitter | clinical testing | This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 682 of the LDLR protein (p.Leu682Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of familial hypercholesterolemia (PMID: 1301956; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as L661P. ClinVar contains an entry for this variant (Variation ID: 252189). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt LDLR protein function. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. |