Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| LDLR- |
RCV000237986 | SCV000294735 | likely pathogenic | Hypercholesterolemia, familial, 1 | 2016-03-25 | criteria provided, single submitter | literature only | |
| Ambry Genetics | RCV002338780 | SCV002640105 | pathogenic | Cardiovascular phenotype | 2023-09-14 | criteria provided, single submitter | clinical testing | The p.C160G pathogenic mutation (also known as c.478T>G), located in coding exon 4 of the LDLR gene, results from a T to G substitution at nucleotide position 478. The cysteine at codon 160, located in LDLR class A repeat 4, is replaced by glycine, 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.C139G, has been reported to segregate with hypercholesterolemia in three individuals in one family, while absent in three individuals with normal total cholesterol (Chakir Kh et al. Mol. Genet. Metab., 1998 Jan;63:31-4). Other variants affecting this codon (p.C160Y, p.C160R, and p.C160F) have also been detected in FH cohorts (Day IN et al. Hum. Mutat., 1997;10:116-27; Amsellem S et al. Hum. Genet., 2002 Dec;111:501-10; Bourbon M et al. Atherosclerosis, 2017 07;262:8-13). Internal structural analysis indicates this alteration eliminates a disulfide bond critical for the structural integrity of LDLR class A repeat 4 (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. |