Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| LDLR- |
RCV000237102 | SCV000295552 | likely pathogenic | Hypercholesterolemia, familial, 1 | 2016-03-25 | criteria provided, single submitter | literature only | |
| Iberoamerican FH Network | RCV000237102 | SCV000748057 | likely pathogenic | Hypercholesterolemia, familial, 1 | 2016-03-01 | criteria provided, single submitter | research | |
| Labcorp Genetics |
RCV001854904 | SCV002228783 | pathogenic | Familial hypercholesterolemia | 2022-07-19 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Gly546 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 17539906, 22859806; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 251947). This variant is also known as p.G525V. This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 15823280, 17539906, 21722902). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 546 of the LDLR protein (p.Gly546Val). |
| Laboratory for Molecular Medicine, |
RCV004017561 | SCV004847787 | likely pathogenic | Homozygous familial hypercholesterolemia | 2019-10-11 | criteria provided, single submitter | clinical testing | The p.Gly546Val variant in LDLR has been reported in 5 individuals with hypercholesterolemia (Koeijvoets 2005, Taylor 2007, Vaca 2011). It was absent from large population studies. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. Another variant, p.Gly546Asp, involving this codon has also been identified in individuals with hypercholesterolemia. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant familial hypercholesterolemia. ACMG/AMP Criteria applied: PM2, PM5, PP3, PS4_Supporting. |
| Clinical Genetics Laboratory, |
RCV004696890 | SCV005198656 | likely pathogenic | not provided | 2022-07-13 | criteria provided, single submitter | clinical testing |