Total submissions: 7
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
LDLR- |
RCV000238228 | SCV000294712 | likely pathogenic | Hypercholesterolemia, familial, 1 | 2016-03-25 | criteria provided, single submitter | literature only | |
Centre de Génétique Moléculaire et Chromosomique, |
RCV000238228 | SCV000503159 | likely pathogenic | Hypercholesterolemia, familial, 1 | 2016-12-16 | criteria provided, single submitter | clinical testing | subject mutated among 2600 FH index cases screened = 1 |
Department of Human Genetics, |
RCV000238228 | SCV000987038 | pathogenic | Hypercholesterolemia, familial, 1 | 2018-10-15 | criteria provided, single submitter | clinical testing | The mutation occurs at protein level at position 148 (position 127 of the mature protein) to change the amino acid cysteine to tyrosine. This change has been reported in the literature, found in patients with familial hypercholesterolemia and is associated with elevated cholesterol and LDL-C levels. It leads to a disturbed LDLR transport from the endoplasmic reticulum to the cell surface or is partially retained in the endoplasmic reticulum (ER). We observed this mutation in a patient with TC up to 380 mg/dl and LDL-C approx 310 mg/dl at the age of 10 years. PMID: 16250003, 1301956, 11462246 |
Ambry Genetics | RCV002327174 | SCV002632585 | pathogenic | Cardiovascular phenotype | 2022-10-20 | criteria provided, single submitter | clinical testing | The p.C148Y pathogenic mutation (also known as c.443G>A), located in coding exon 4 of the LDLR gene, results from a G to A substitution at nucleotide position 443. The cysteine at codon 148 is replaced by tyrosine, an amino acid with highly dissimilar properties. Pathogenic LDLR mutations that result in the substitution or generation of cysteine residues within the cysteine-rich LDLR class A repeats and EGF-like domains are common in familial hypercholesterolemia (FH) (Villéger L. Hum Mutat. 2002;20(2):81-7). This variant (also referred to as C127Y) has been detected in several unrelated individuals with familial hypercholesterolemia (FH) and FH cohorts (Nauck MS et al. Hum Mutat, 2001 Aug;18:165-6; Fouchier SW et al. Hum Mutat, 2005 Dec;26:550-6; Humphries SE et al. J Mol Med (Berl), 2006 Mar;84:203-14; Taylor A et al. Clin Genet, 2007 Jun;71:561-8; Moradi A et al. Front Genet, 2021 Feb;12:625959). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Other variants affecting this codon, including p.C148S (c.443G>C), have also been reported in association with FH (Slimane MN et al. J Med Genet, 2002 Nov;39:e74). Internal structural analysis indicates this variant eliminates a disulfide bond critical for the structural integrity of LDLR class A repeat 4 (Ambry internal data). 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. |
Invitae | RCV002518475 | SCV003443865 | pathogenic | Familial hypercholesterolemia | 2023-06-24 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. This variant affects a cysteine residue located within an LDLRA or epidermal-growth-factor (EGF)-like domains of the LDLR protein. Cysteine residues in these domains have been shown to be involved in the formation of disulfide bridges, which are critical for protein structure and stability (PMID: 7548065, 7603991, 7979249). In addition, missense substitutions within the LDLRA and EGF-like domains affecting cysteine residues are overrepresented among patients with hypercholesterolemia (PMID: 18325082). 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. ClinVar contains an entry for this variant (Variation ID: 251225). This variant is also known as C127Y. This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 11462246, 16389549, 17539906, 33732287). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 148 of the LDLR protein (p.Cys148Tyr). |
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, |
RCV000238228 | SCV000606120 | pathogenic | Hypercholesterolemia, familial, 1 | no assertion criteria provided | research | ||
Rajaie Cardiovascular, |
RCV000238228 | SCV001467722 | pathogenic | Hypercholesterolemia, familial, 1 | no assertion criteria provided | research |