Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| LDLR- |
RCV000238099 | SCV000295298 | likely pathogenic | Hypercholesterolemia, familial, 1 | 2016-03-25 | criteria provided, single submitter | literature only | |
| Ambry Genetics | RCV002347940 | SCV002648251 | uncertain significance | Cardiovascular phenotype | 2019-09-13 | criteria provided, single submitter | clinical testing | The p.F403L variant (also known as c.1207T>C and F382L), located in coding exon 9 of the LDLR gene, results from a T to C substitution at nucleotide position 1207. The phenylalanine at codon 403 is replaced by leucine, an amino acid with highly similar properties. This alteration has been been detected in individuals from familial hypercholesterolemia cohorts; however clinical details were limited (Varret M et al. Nucleic Acids Res., 1998 Jan;26:248-52; Hattori H et al. Hum. Mutat., 1999;14:87; Kim JH et al. Mol. Cells, 2004 Aug;18:63-70; Miyake Y et al. Atherosclerosis, 2009 Mar;203:153-60). 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. |
| Labcorp Genetics |
RCV005090230 | SCV005837091 | pathogenic | Familial hypercholesterolemia | 2024-06-02 | criteria provided, single submitter | clinical testing | This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 403 of the LDLR protein (p.Phe403Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hypercholesterolemia (PMID: 10447263, 15359125, 31491741, 33740630, 35480308; Invitae). ClinVar contains an entry for this variant (Variation ID: 251732). 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%. For these reasons, this variant has been classified as Pathogenic. |
| Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, |
RCV000238099 | SCV000606359 | pathogenic | Hypercholesterolemia, familial, 1 | no assertion criteria provided | research |