Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| LDLR- |
RCV000237550 | SCV000294576 | likely pathogenic | Hypercholesterolemia, familial, 1 | 2016-03-25 | criteria provided, single submitter | literature only | |
| Arcensus | RCV000237550 | SCV002564608 | pathogenic | Hypercholesterolemia, familial, 1 | 2013-02-01 | criteria provided, single submitter | clinical testing | |
| Ambry Genetics | RCV002436070 | SCV002751749 | pathogenic | Cardiovascular phenotype | 2022-05-27 | criteria provided, single submitter | clinical testing | The p.C95R pathogenic mutation (also known as c.283T>C), located in coding exon 3 of the LDLR gene, results from a T to C substitution at nucleotide position 283. The cysteine at codon 95, located in LDLR class A repeat 2, is replaced by arginine, 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 particular cysteine alteration (also referred to as p.C74R) has been detected in several individuals with FH (Deiana L et al. Arterioscler Thromb Vasc Biol, 2000 Jan;20:236-43; Fouchier SW et al. Hum Mutat, 2005 Dec;26:550-6; Blesa S et al. Clin Chem, 2006 Jun;52:1021-5; Vandrovcova J et al. Genet Med, 2013 Dec;15:948-57). Internal structural analysis indicates this alteration eliminates a disulfide bond critical for the structural integrity of LDLR class A repeat 2 (Ambry internal data). A different variant affecting this codon (p.C95F, c.284G>T) has also been reported in association with FH (Miyake Y et al. Atherosclerosis, 2009 Mar;203:153-60). This variant is considered to be rare based on population 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. |
| Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, |
RCV000237550 | SCV000606061 | pathogenic | Hypercholesterolemia, familial, 1 | no assertion criteria provided | research |