Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Clin |
RCV000237957 | SCV005328525 | likely pathogenic | Hypercholesterolemia, familial, 1 | 2023-06-23 | reviewed by expert panel | curation | The NM_000527.5(LDLR):c.1445A>G (p.Asp482Gly) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2, PM5, PP3 and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 23 June 2023. The supporting evidence is as follows: PM2: This variant is absent from gnomAD (gnomAD v2.1.1). PP3: REVEL=0.987. PM5: 3 other missense variants in the same codon: - NM_000527.5(LDLR):c.1444G>A (p.Asp482Asn) (ClinVar ID 161284) - Pathogenic by these guidelines; - NM_000527.5(LDLR):c.1444G>T (p.Asp482Tyr) (ClinVar ID 251845) - Uncertain significance by these guidelines; - NM_000527.5(LDLR):c.1444G>C (p.Asp482His) (ClinVar ID 251844) - Likely Pathogenic by these guidelines; There is 1 variant in the same codon classified as Pathogenic by these guidelines. PP4: Variant meets PM2 and is identified in 1 index case who fulfills WHO criteria for FH from PMID 20145306 (Chmara M et al., 2010), after alternative causes of high cholesterol were excluded. |
| LDLR- |
RCV000237957 | SCV000295436 | likely pathogenic | Hypercholesterolemia, familial, 1 | 2016-03-25 | criteria provided, single submitter | literature only | |
| Labcorp Genetics |
RCV003581626 | SCV004298360 | likely pathogenic | Familial hypercholesterolemia | 2023-11-13 | criteria provided, single submitter | clinical testing | This sequence change replaces aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 482 of the LDLR protein (p.Asp482Gly). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with familial hypercholesterolemia (PMID: 20145306; Invitae). ClinVar contains an entry for this variant (Variation ID: 251846). 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 with a positive predictive value of 95%. This variant disrupts the p.Asp482 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8535447, 16389549, 20236128, 21310417, 23375686). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. |