Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV002233390 | SCV000831992 | likely pathogenic | Familial hypercholesterolemia | 2018-06-12 | criteria provided, single submitter | clinical testing | Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has been reported to segregate with hypercholesterolemia in a single family (Invitae) and observed in an unrelated affected individual (PMID: 26802169). This variant is not present in population databases (ExAC no frequency). This sequence change replaces cysteine with phenylalanine at codon 325 of the LDLR protein (p.Cys325Phe). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and phenylalanine. This variant affects a cysteine residue located within an epidermal-growth-factor (EGF)–like domain of the LDLR protein. Cysteine residues in these domains have been shown to be involved in the formation of disulfide bridges, which are critical for protein structure and stability (PMID: 3495735, 4750422). In addition, missense substitutions within the LDLR EGF-like domains affecting cysteine residues are overrepresented among patients with hypercholesterolemia (PMID: 18325082). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. |
| Ambry Genetics | RCV003303184 | SCV004000134 | likely pathogenic | Cardiovascular phenotype | 2023-04-18 | criteria provided, single submitter | clinical testing | The p.C325F variant (also known as c.974G>T), located in coding exon 7 of the LDLR gene, results from a G to T substitution at nucleotide position 974. The cysteine at codon 325 is replaced by phenylalanine, an amino acid with highly dissimilar properties. This alteration has been reported in subjects with features of familial hypercholesterolemia (FH) (Sturm AC et al. JAMA Cardiol, 2021 Aug;6:902-909; Wintjens R et al. J Lipid Res, 2016 Mar;57:482-91). 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 variant eliminates a disulfide bond critical for the structural integrity of the EGF-like 1 domain (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Another alteration at the same codon, p.C325Y (c.974G>A), has been described in association with FH (Alonso R et al. Clin Biochem. 2009;42:899-903). 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. |