Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Color Diagnostics, |
RCV001179446 | SCV001344107 | likely pathogenic | Familial hypercholesterolemia | 2019-02-26 | criteria provided, single submitter | clinical testing | This missense variant (also known as p.Cys122Ser in the mature protein) is located in the LDLR type A repeat 3 of the ligand binding domain of the LDLR protein. Although functional assays have not been performed, this variant changes one of the functionally critical cysteine residues that form intra-repeat disulfide bonds in the ligand binding domain (PMID: 15952897) and is expected to have deleterious impact on the LDLR protein folding and stability. Computational splicing tools suggest that this variant may not impact RNA splicing. This variant has been identified in individuals with familial hypercholesterolemia (PMID: 27765764, 28964736). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). In addition, different variants occurring at the same amino acid position (p.Cys143Arg, p.Cys143Gly, p.Cys143Tyr) are considered deleterious (Clinvar), suggesting that cysteine at this position is important for the LDLR function. Based on available evidence, this variant is classified as Likely Pathogenic. |
| Labcorp Genetics |
RCV001179446 | SCV003483488 | pathogenic | Familial hypercholesterolemia | 2022-05-03 | criteria provided, single submitter | clinical testing | This variant is not present in population databases (gnomAD no frequency). This sequence change replaces cysteine, which is neutral and slightly polar, with serine, which is neutral and polar, at codon 143 of the LDLR protein (p.Cys143Ser). This missense change has been observed in individuals with LDLR-related conditions (PMID: 28964736, 30592178, 33303402, 33740630, 34040191; Invite). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Cys143 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been observed in individuals with LDLR-related conditions (PMID: 11462246, 20809525, 22698793; Invitae), which suggests that this may be a clinically significant amino acid residue. This variant affects a cysteine residue located within an LDLRA or epidermal-growth-factor (EGF)-like domains 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: 7548065, 7603991, 7979249). In addition, missense substitutions within the LDLRA and EGF-like domains affecting cysteine residues are overrepresented among patients with hypercholesterolemia (PMID: 18325082). 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. ClinVar contains an entry for this variant (Variation ID: 920596). |
| Ambry Genetics | RCV004033034 | SCV003967591 | pathogenic | Cardiovascular phenotype | 2023-05-23 | criteria provided, single submitter | clinical testing | The c.427T>A (p.C143S) alteration is located in exon 4 (coding exon 4) of the LDLR gene. This alteration results from a T to A substitution at nucleotide position 427, causing the cysteine (C) at amino acid position 143 to be replaced by a serine (S). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant has been detected in individuals reported to have familial hypercholesterolemia (FH) (Defesche, 2017; Wang, 2016; Ajufo, 2021). Another alteration at the same codon, c.428G>A (p.C143Y), has also been reported in association with FH (Kim, 2018). This amino acid position is highly conserved in available vertebrate species. 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 FH (Villéger, 2002). Internal structural analysis indicates this variant eliminates a disulfide bond critical for the structural integrity of the LDLR class A repeat 3domain (Ambry internal data). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. |