Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Clin |
RCV000237644 | SCV002568116 | uncertain significance | Hypercholesterolemia, familial, 1 | 2022-01-18 | reviewed by expert panel | curation | NM_000527.5(LDLR):c.1576C>A (p.Pro526Thr) variant is classified as variant of Uncertain significance for Familial Hypercholesterolemia by applying evidence codes (PM2, PP3 and PP4) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: PM2 - This variant is absent from gnomAD (gnomAD v2.1.1). PP3 - REVEL = 0.951. PP4 - Variant meets PM2. Identified in 1 FH case with clinical diagnosis of probable heterozygous hypercholesterolemia by DLCN score (DLCN = 8) from PMID 32770674. |
| LDLR- |
RCV000237644 | SCV000295504 | likely pathogenic | Hypercholesterolemia, familial, 1 | 2016-03-25 | criteria provided, single submitter | literature only | |
| Labcorp Genetics |
RCV002519849 | SCV003443164 | pathogenic | Familial hypercholesterolemia | 2024-09-11 | criteria provided, single submitter | clinical testing | This sequence change replaces proline, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 526 of the LDLR protein (p.Pro526Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 32770674; internal data). ClinVar contains an entry for this variant (Variation ID: 251903). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt LDLR protein function with a positive predictive value of 95%. This variant disrupts the p.Pro526 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 1301956, 9259195, 11462246, 27497240; internal data). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. |