Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| LDLR- |
RCV000238340 | SCV000294870 | likely pathogenic | Hypercholesterolemia, familial, 1 | 2016-03-25 | criteria provided, single submitter | literature only | |
| Fundacion Hipercolesterolemia Familiar | RCV000238340 | SCV000607484 | likely pathogenic | Hypercholesterolemia, familial, 1 | 2016-03-01 | criteria provided, single submitter | research | |
| Ambry Genetics | RCV002362855 | SCV002663276 | pathogenic | Cardiovascular phenotype | 2024-07-03 | criteria provided, single submitter | clinical testing | The p.C222Y pathogenic mutation (also known as c.665G>A), located in coding exon 4 of the LDLR gene, results from a G to A substitution at nucleotide position 665. The cysteine at codon 222, is replaced by tyrosine, an amino acid with highly dissimilar properties. This variant (also referred to as p.C201Y) has been detected in multiple individuals with features consistent with familial hypercholesterolemia (FH) (Koivisto UM et al. Am J Hum Genet, 1995 Oct;57:789-97; Bertolini S et al. Arterioscler Thromb Vasc Biol, 2000 Sep;20:E41-52; Alonso R et al. Clin Biochem, 2009 Jun;42:899-903; Chmara M et al. J Appl Genet, 2010;51:95-106; Thormaehlen AS et al. PLoS Genet, 2015 Feb;11:e1004855; Do R et al. Nature, 2015 Feb;518:102-6). In in vitro assays from one group, this variant was indicated to disrupt protein function (Thormaehlen AS et al. PLoS Genet, 2015 Feb;11:e1004855). 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). 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.C222R, c.664T>C) has also been reported in association with FH (Damgaard D et al. Atherosclerosis. 2005;180:155-60). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. |
| GENin |
RCV005365054 | SCV005921957 | pathogenic | Familial hypercholesterolemia | 2023-12-13 | criteria provided, single submitter | clinical testing | The LDLR c.665G>A p.(Cys222Tyr) variant has been seen in >=10 FH patients meeting clinical criteria, including after alternative causes of high cholesterol were excluded (PS4_STRONG, PP4_SUPPORTING; PMIDs 7573037, 10978268, 20145306, 23375686, 38122934). The highest population minor allele frequency in gnomAD v2.1.1 is 0.000008863 in European (non-Finnish) population, which is lower than the ClinGen FH VCEP threshold (=<0.0002), so PM2_MODERATE is met. This is a missense change of a highly conserved cysteine residue and meets PM2 (PM1_MODERATE). A level 3 functional assay showed reduced expression and activity compared to wild type (PS3_SUPPORTING; PMID 25647241) and the REVEL score is 0.951 (PP3_SUPPORTING). Based on the evidence listed above, we have classified this variant as Pathogenic. |
| Dept. |
RCV000161963 | SCV000189538 | not provided | not provided | no assertion provided | in vitro |