Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Clin |
RCV000508695 | SCV004022410 | uncertain significance | Hypercholesterolemia, familial, 1 | 2023-04-29 | reviewed by expert panel | curation | The NM_000527.5(LDLR):c.1449G>C (p.Trp483Cys) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (PM2, PP3) 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), so PM2 is Met. PP3 - REVEL = 0.951. It is above 0.75, so PP3 is Met. |
| Labcorp Genetics |
RCV001034671 | SCV000815123 | pathogenic | Familial hypercholesterolemia | 2019-11-29 | criteria provided, single submitter | clinical testing | This variant disrupts the p.Trp483 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8535447, 17539906, 21382890, 16250003). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. This sequence change replaces tryptophan with cysteine at codon 483 of the LDLR protein (p.Trp483Cys). The tryptophan residue is highly conserved and there is a large physicochemical difference between tryptophan and cysteine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individual(s) with hypercholesterolemia (PMID: 26892515, Invitae). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 440646). 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. For these reasons, this variant has been classified as Pathogenic. |
| Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, |
RCV000508695 | SCV000606432 | pathogenic | Hypercholesterolemia, familial, 1 | no assertion criteria provided | research |