Total submissions: 6
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Clin |
RCV000238428 | SCV004022464 | likely pathogenic | Hypercholesterolemia, familial, 1 | 2023-04-28 | reviewed by expert panel | curation | The NM_000527.5(LDLR):c.727T>C (p.Cys243Arg) variant is classified as likely pathogenic for Familial Hypercholesterolemia by applying evidence code PM1, PM2, PP3, PP4 and 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: PM2 - This variant is absent from gnomAD (gnomAD v2.1.1). PP3 - REVEL = 0.966 PM1 - Variant meets PM2 and alters Cys243, one of the cysteine residues listed. PS4_Supporting - Variant meets PM2 and is identified in 2 index cases who fullfill DLCN>=6 criteria for FH from Research Lab of Molecular Genetics of Lipid Metabolism and PMID: 28502510. PP4 - Variant meets PM2 and is identified in 2 index cases who fullfill DLCN>=6 criteria for FH from Research Lab of Molecular Genetics of Lipid Metabolism after alternative cause of high cholesterol were excluded. |
LDLR- |
RCV000238428 | SCV000294942 | likely pathogenic | Hypercholesterolemia, familial, 1 | 2016-03-25 | criteria provided, single submitter | literature only | |
Iberoamerican FH Network | RCV000238428 | SCV000748088 | uncertain significance | Hypercholesterolemia, familial, 1 | 2016-03-01 | criteria provided, single submitter | research | |
Labcorp Genetics |
RCV000802806 | SCV000942651 | pathogenic | Familial hypercholesterolemia | 2023-07-10 | criteria provided, single submitter | clinical testing | ClinVar contains an entry for this variant (Variation ID: 251425). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt LDLR protein function. 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). For these reasons, this variant has been classified as Pathogenic. This variant is also known as p.Cys222Arg. This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 243 of the LDLR protein (p.Cys243Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 10532689, 28502510, 31491741; Invitae). |
Women's Health and Genetics/Laboratory Corporation of America, |
RCV001264593 | SCV001442821 | uncertain significance | not specified | 2020-10-19 | criteria provided, single submitter | clinical testing | Variant summary: LDLR c.727T>C (p.Cys243Arg) results in a non-conservative amino acid change located in the Low-density lipoprotein (LDL) receptor class A repeat (IPR002172) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251490 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.727T>C has been reported in the literature in individuals affected with Familial Hypercholesterolemia (both heterozygous and compound heterozygous) (Banares_2017, DiTaranto_2020, Hori_2019, Jensen_1999. These reports however, do not provide unequivocal conclusions about association of the variant with Familial Hypercholesterolemia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (n=2) or likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance. |
Amrita Institute of Medical Sciences and Research Centre, |
RCV000238428 | SCV005205809 | likely pathogenic | Hypercholesterolemia, familial, 1 | 2023-01-01 | no assertion criteria provided | clinical testing | This variant(LDLR):c.727T>C (p.Cys243Arg) variant is classified as likely pathogenic for Familial Hypercholesterolemia by applying PM1, PM2, PP3, PP4 and PS4_Supporting as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines |