Total submissions: 14
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
LDLR- |
RCV000237699 | SCV000294955 | likely pathogenic | Hypercholesterolemia, familial, 1 | 2016-03-25 | criteria provided, single submitter | literature only | |
Centre de Génétique Moléculaire et Chromosomique, |
RCV000237699 | SCV000503231 | likely pathogenic | Hypercholesterolemia, familial, 1 | 2016-12-16 | criteria provided, single submitter | clinical testing | subject mutated among 2600 FH index cases screened = 1 / previously described in association with FH / Software predictions: Conflicting |
Molecular Genetics Laboratory, |
RCV000237699 | SCV000540757 | likely pathogenic | Hypercholesterolemia, familial, 1 | 2016-11-05 | criteria provided, single submitter | clinical testing | |
U4M - |
RCV000237699 | SCV000583736 | pathogenic | Hypercholesterolemia, familial, 1 | 2017-03-30 | criteria provided, single submitter | clinical testing | |
Laboratory for Molecular Medicine, |
RCV000844739 | SCV000712914 | likely pathogenic | Homozygous familial hypercholesterolemia | 2017-03-13 | criteria provided, single submitter | clinical testing | The p.Gln254Pro variant in LDLR has been reported in the heterozygous state in 9 individuals with familial hypercholesterolemia, as well as one homozygote (Bert olini 2000, Dedoussis 2004, Brusgaard 2006, Diakou 2011, Tichy 2012, Bertolini 2 013. In addition, this variant has been reported in a consanguineous family alon g with a second hypercholesterolemia variant (LDLRAP1 p.Gly136X). In this family , disease severity correlated with the various combinations of heterozygosity or homozygosity for the two variants (Soufi 2013). The p.Gln254Pro variant has als o been reported in ClinVar (Variation ID 251437) and was absent from large popul ation studies. In summary, although additional studies are required to fully est ablish its clinical significance, the p.Gln254Pro variant is likely pathogenic. |
Department of Human Genetics, |
RCV000237699 | SCV000987041 | pathogenic | Hypercholesterolemia, familial, 1 | 2018-12-19 | criteria provided, single submitter | clinical testing | The mutation at protein level leads to an amino acid exchange of glutamine to proline at position 254 (233rd amino acid of the mature protein) in the LDL receptor. This change has already been described in the literature as FH Reggio Emilia-2, as well as in patients with familial hypercholesterolaemia. We observed this variant in a patient with TC up to 360 mg/dl and LDL-C approx 300 mg/dl at the age of 55. PMID: 14974088, 11754108, 23375686 |
Color Diagnostics, |
RCV001190236 | SCV001357683 | pathogenic | Familial hypercholesterolemia | 2019-10-10 | criteria provided, single submitter | clinical testing | This missense variant (also known as p.Gln233Pro in the mature protein and as FH-Reggio Emilia-2) replaces glutamine with proline at codon 254 in the LDLR type A repeat 6 of ligand binding domain of the LDLR protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. A functional study has shown that this variant does not affect protein expression at the cellular surface but reduces LDL binding and internalization activity by 80% compared to wild type protein (PMID: 31578082). This variant has been reported in over ten individuals affected with familial hypercholesterolemia (PMID: 10978268, 11754108, 14974088, 15200491, 16542394, 19446849, 21925044, 22698793, 23375686, 30415195). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. |
Invitae | RCV001190236 | SCV001393260 | pathogenic | Familial hypercholesterolemia | 2023-10-22 | criteria provided, single submitter | clinical testing | This sequence change replaces glutamine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 254 of the LDLR protein (p.Gln254Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 10978268, 11754108, 14974088, 19319977, 19446849, 21925044, 25463123). This variant is also known as Q233P and FH Reggio Emilia-2. ClinVar contains an entry for this variant (Variation ID: 251437). 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. This variant disrupts the p.Gln233 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been observed in individuals with LDLR-related conditions (PMID: 16250003), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. |
Laboratory of molecular diagnosis of dyslipidemias, |
RCV000237699 | SCV001653608 | likely pathogenic | Hypercholesterolemia, familial, 1 | 2021-05-24 | criteria provided, single submitter | clinical testing | |
Human Genome Sequencing Center Clinical Lab, |
RCV000237699 | SCV001754783 | likely pathogenic | Hypercholesterolemia, familial, 1 | 2019-09-26 | criteria provided, single submitter | clinical testing | The c.761A>C (p.Gln254Pro) variant in the LDLR gene has been described as FH Reggio Emilia-2 in the literature (PMID: 10978268) and reported in multiple unrelated individuals with familial hypercholesterolemia (PMID: 10978268, 11754108, 14974088, 15200491, 16542394, 19446849, 21925044, 23375686, 23510778). This variant is absent from general population databases. Multiple lines of in silico algorithms have predicted this p.Gln254Pro change to be deleterious. Therefore, this c.761A>C (p.Gln254Pro) variant is classified as likely pathogenic. |
Revvity Omics, |
RCV000237699 | SCV002017110 | pathogenic | Hypercholesterolemia, familial, 1 | 2022-04-21 | criteria provided, single submitter | clinical testing | |
Ambry Genetics | RCV002392740 | SCV002673773 | pathogenic | Cardiovascular phenotype | 2020-10-06 | criteria provided, single submitter | clinical testing | The p.Q254P pathogenic mutation (also known as c.761A>C), located in coding exon 5 of the LDLR gene, results from an A to C substitution at nucleotide position 761. The glutamine at codon 254 is replaced by proline, an amino acid with similar properties. This alteration has been reported in multiple individuals of various ethnic backgrounds with familial hypercholesterolemia (Bertolini S et al. Atherosclerosis, 2013 Apr;227:342-8; Kuhrová V et al. Hum. Mutat., 2002 Jan;19:80; Dedoussis GV et al. Hum. Mutat., 2004 Mar;23:285-6; Brusgaard K et al. Clin. Genet., 2006 Mar;69:277-83; Abifadel M et al. Hum. Mutat., 2009 Jul;30:E682-91; Soufi M et al. Gene, 2013 May;521:200-3; Mollaki V et al. Atherosclerosis, 2014 Dec;237:798-804). Functional studies demonstrated reduced LDL binding and uptake (Banerjee P et al. Arterioscler. Thromb. Vasc. Biol., 2019 11;39:2248-2260). Based on internal structural analysis, this variant is anticipated to result in a significant decrease in ligand binding and structure stability (Rudenko G et al. Science, 2002 Dec;298:2353-8). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. |
Fulgent Genetics, |
RCV000237699 | SCV002790803 | pathogenic | Hypercholesterolemia, familial, 1 | 2022-03-29 | criteria provided, single submitter | clinical testing | |
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, |
RCV000237699 | SCV000606217 | pathogenic | Hypercholesterolemia, familial, 1 | no assertion criteria provided | research |