Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Fundacion Hipercolesterolemia Familiar | RCV000509474 | SCV000607463 | likely pathogenic | Hypercholesterolemia, familial, 1 | 2016-03-01 | criteria provided, single submitter | research | |
| Ambry Genetics | RCV002341198 | SCV002638378 | likely pathogenic | Cardiovascular phenotype | 2020-03-31 | criteria provided, single submitter | clinical testing | The p.C160F variant (also known as c.479G>T), located in coding exon 4 of the LDLR gene, results from a G to T substitution at nucleotide position 479. The cysteine at codon 160, located in LDLR class A repeat 4, is replaced by phenylalanine, 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 C139F, has been detected in an FH cohort; however, details were limited (Bourbon M et al. Atherosclerosis, 2017 07;262:8-13). Other variants affecting this codon (p.C160Y, p.C160G, and p.C160R) have also been detected in FH cohorts (Day IN et al. Hum. Mutat., 1997;10:116-27; Chakir Kh et al. Mol. Genet. Metab., 1998 Jan;63:31-4; Amsellem S et al. Hum. Genet., 2002 Dec;111:501-10 ). 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 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. |