ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.727T>C (p.Cys243Arg)

dbSNP: rs879254659
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel 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-LOVD, British Heart Foundation 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 (formerly Invitae), Labcorp 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, LabCorp 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, Amrita Vishwa Vidyapeetham 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

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