Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| LDLR- |
RCV000238105 | SCV000294844 | likely pathogenic | Hypercholesterolemia, familial, 1 | 2016-03-25 | criteria provided, single submitter | literature only | |
| Centre de Génétique Moléculaire et Chromosomique, |
RCV000238105 | SCV000503194 | likely pathogenic | Hypercholesterolemia, familial, 1 | 2016-12-16 | criteria provided, single submitter | clinical testing | subject mutated among 2600 FH index cases screened = 1 , family member = 1 with co-segregation / previously described in association with FH and other mutation at same codon / Software predictions: Damaging |
| Fundacion Hipercolesterolemia Familiar | RCV000238105 | SCV000607478 | likely pathogenic | Hypercholesterolemia, familial, 1 | 2016-03-01 | criteria provided, single submitter | research | |
| Iberoamerican FH Network | RCV000238105 | SCV000748086 | likely pathogenic | Hypercholesterolemia, familial, 1 | 2016-03-01 | criteria provided, single submitter | research | |
| Ambry Genetics | RCV002356333 | SCV002654756 | likely pathogenic | Cardiovascular phenotype | 2021-10-04 | criteria provided, single submitter | clinical testing | The p.C216R variant (also known as c.646T>C), located in coding exon 4 of the LDLR gene, results from a T to C substitution at nucleotide position 646. The cysteine at codon 216, located in LDLR class A repeat 5, 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 change (also referred to as p.C195R) has been detected in individuals from FH cohorts; however, some reports may overlap (Mozas P et al. Hum Mutat, 2004 Aug;24:187; Junyent M et al. Arterioscler Thromb Vasc Biol, 2008 Mar;28:580-6; Corral P et al. Atherosclerosis, 2018 10;277:256-261; Corral P et al. Arch Cardiol Mex, 2020;90:130-136). Internal structural analysis indicates this alteration eliminates a disulfide bond critical for the structural integrity of the LDLR class A repeat 5 (Ambry internal data). Another variant affecting this codon (p.C216Y, c.647G>A) has also been reported in association with FH (Dedoussis GV et al. Hum Mutat, 2004 Mar;23:285-6). 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 majority of available evidence to date, this variant is likely to be pathogenic. |