Total submissions: 6
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Clin |
RCV000237208 | SCV004022427 | likely pathogenic | Hypercholesterolemia, familial, 1 | 2023-04-28 | reviewed by expert panel | curation | The NM_000527.5(LDLR):c.665G>T (p.Cys222Phe) variant is classified as Likely pathogenic for Familial Hypercholesterolemia by applying evidence codes PM1, PM2, PS3_Moderate, PP3, PP4, PS4_Supporting as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: PM1: Variant meets PM2 and is missense in exon 4 PM2: This variant is absent from gnomAD v 2.1.1. PS3_Moderate: PMID: 24671153 Heterologous cells, 30 % cell surface LDLR and internalization PP3: REVEL is 0.971, which is greater than 0.75. PP4: Variant meets PM2 and is identified in at least 1 index case who fulfills DLCN>=6 criteria for FH from PMID 24671153, after alternative causes of high cholesterol were excluded.. PS4_Supporting: Variant meets PM2 and is identified in at least 2 unrelated index cases. 1 index case from PMID 11810272 who fulfilled unspecified clinical criteria for FH, and 1 index case from PMID 24671153 who fulfilled DLCN>6 criteria for FH. |
| LDLR- |
RCV000237208 | SCV000294871 | likely pathogenic | Hypercholesterolemia, familial, 1 | 2016-03-25 | criteria provided, single submitter | literature only | |
| Centre de Génétique Moléculaire et Chromosomique, |
RCV000237208 | SCV000503202 | likely pathogenic | Hypercholesterolemia, familial, 1 | 2016-12-16 | criteria provided, single submitter | clinical testing | subject mutated among 2600 FH index cases screened = 1 / Software predictions: Damaging |
| Fundacion Hipercolesterolemia Familiar | RCV000237208 | SCV000607485 | pathogenic | Hypercholesterolemia, familial, 1 | 2016-03-01 | criteria provided, single submitter | research | |
| Labcorp Genetics |
RCV001376811 | SCV001573983 | likely pathogenic | Familial hypercholesterolemia | 2020-06-22 | criteria provided, single submitter | clinical testing | This variant has been observed in individual(s) with clinical features of familial hypercholesterolemia (PMID: 11810272, 24671153, 27830735, 30526649). ClinVar contains an entry for this variant (Variation ID: 251362). 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). This variant is not present in population databases (ExAC no frequency). This sequence change replaces cysteine with phenylalanine at codon 222 of the LDLR protein (p.Cys222Phe). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and phenylalanine. 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. This variant disrupts the p.Cys222 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been observed in individuals with LDLR-related conditions (PMID: 25043216, 7573037), which suggests that this may be a clinically significant amino acid residue. |
| Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, |
RCV000237208 | SCV000606189 | pathogenic | Hypercholesterolemia, familial, 1 | no assertion criteria provided | research |