ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.590G>A (p.Cys197Tyr) (rs376459828)

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Total submissions: 16
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
LDLR-LOVD, British Heart Foundation RCV000237811 SCV000294806 likely pathogenic Familial hypercholesterolemia 1 2016-03-25 criteria provided, single submitter literature only
Robarts Research Institute,Western University RCV000237811 SCV000484712 likely pathogenic Familial hypercholesterolemia 1 criteria provided, single submitter clinical testing
Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies,APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix RCV000237811 SCV000503184 likely pathogenic Familial hypercholesterolemia 1 2016-12-16 criteria provided, single submitter clinical testing subject mutated among 2600 FH index cases screened = 1 /FH-El-Savador, <2% activy LDLR / Software predictions: Damaging
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille RCV000237811 SCV000583705 pathogenic Familial hypercholesterolemia 1 2017-03-30 criteria provided, single submitter clinical testing
Fundacion Hipercolesterolemia Familiar RCV000237811 SCV000607475 likely pathogenic Familial hypercholesterolemia 1 2016-03-01 criteria provided, single submitter research
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000589041 SCV000697242 pathogenic Familial hypercholesterolemia 2019-03-04 criteria provided, single submitter clinical testing Variant summary: LDLR c.590G>A (p.Cys197Tyr), also known as FH-El Salvador-1, results in a non-conservative amino acid change located in the Low-density lipoprotein (LDL) receptor class A repeat domain (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 246122 control chromosomes. c.590G>A has been reported in the literature in multiple individuals affected with Familial Hypercholesterolemia (Hobbs_1992; Ahmad_2012; Junyent_2010; Setia_2016; Chious_2011; Martin-Campos_2018). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <2% of normal LDLR activity (Hobbs_1992). Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Iberoamerican FH Network RCV000237811 SCV000748112 likely pathogenic Familial hypercholesterolemia 1 2016-03-01 criteria provided, single submitter research
Invitae RCV000589041 SCV000752405 pathogenic Familial hypercholesterolemia 2020-10-20 criteria provided, single submitter clinical testing This sequence change replaces cysteine with tyrosine at codon 197 of the LDLR protein (p.Cys197Tyr). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and tyrosine. This variant is not present in population databases (ExAC no frequency). This variant has been reported as heterozygous, homozygous or in combination with another LDLR variant in multiple individuals affected with familial hypercholesterolemia (PMID: 1301956, 27816806, 23064986, 18096825, 21276076, 20538126, 27765764). This variant is also known as C176Y in the literature. ClinVar contains an entry for this variant (Variation ID: 200919). This variant affects a cysteine residue located within an LDLRA 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: 7548065, 7603991, 7979249). In addition, missense substitutions within the LDLRA domains affecting cysteine residues are overrepresented among patients with hypercholesterolemia (PMID: 18325082). A different missense substitution at this codon (p.Cys197Gly) has been determined to be pathogenic (PMID: 20809525, 24014831), while two other missense substitutions at this codon (p.Cys197Arg and p.Cys197Phe) have been reported in individuals affected with familial hypercholesterolemia (PMID: 9026534, 20828696). This suggests that the cysteine residue is critical for LDLR protein function and that other missense substitutions at this position may also be pathogenic. For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000826174 SCV000967713 likely pathogenic Homozygous familial hypercholesterolemia 2018-02-07 criteria provided, single submitter clinical testing The p.Cys197Tyr variant in LDLR (also described as p.Cys176Tyr in the literature ) has been reported in at least 3 individuals with familial hypercholesterolemia (FH) in the heterozygous, homozygous, and compound heterozygous states (Hobbs 1 992, Chiou 2010, Setia 2016, ClinVar: Variation ID 200919). The variant segregat ed with disease in at least 1 affected relative (homozygous FH) from 1 family (S etia 2016). This variant was absent from large population studies. Computational prediction tools and conservation analysis suggest that the p.Cys197Tyr variant may impact the protein. In addition, other variants at this position (p.Cys197T rp, p.Cys197Cys, p.Cys197Arg, p.Cys197Phe, p.Cys197Gly) have been reported in in dividuals with FH (Clinvar, HGMD database; Stenson 2017), suggesting that change s at this position are not tolerated. In summary, although additional studies ar e required to fully establish its clinical significance, the p.Cys197Tyr variant is likely pathogenic. ACMG/AMP Criteria applied: PS4_Supporting, PP3, PM2, PM5.
Color Health, Inc RCV000589041 SCV001358756 pathogenic Familial hypercholesterolemia 2021-02-02 criteria provided, single submitter clinical testing This missense variant (also known as p.Cys176Tyr in the mature protein and as FH El Salvador-1) is located in the LDLR type A repeat 5 of ligand binding domain of the LDLR protein. 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. Cells from an individual compound heterozygous for this variant and p.Gln678* showed <2% LDLR activity (PMID: 1301956). This variant has been reported in over ten individuals affected with familial hypercholesterolemia (PMID: 1301956, 18096825, 20538126, 21376320, 23064986, 27765764, 27816806, 28502495, 32044282). This variant has been reported in five heterozygous and two homozygous individuals from a family affected with familial hypercholesterolemia, with the two homozygotes having coronary artery disease and myocardial infarction (PMID: 27816806). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Different missense variants occurring at the same amino acid position (p.Cys197Gly, p.Cys197Phe, and p.Cys197Trp) are known to be disease-causing (ClinVar variation ID: 251308, 251309, 251311), indicating that cysteine at this position is important for LDLR function. Based on the available evidence, this variant is classified as Pathogenic.
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine RCV000589041 SCV001434985 likely pathogenic Familial hypercholesterolemia 2018-10-12 criteria provided, single submitter clinical testing The novel missense variant, c.590G>A (p.Cys197Tyr), in the LDLR gene has been observed in multiple unrelated probands with familial hypercholesterolemia (PMID 1301956, 18096825, 20538126, 2306498, 27765764, 27816806). This variant in ligand binding domain and other variants in the same codon (Cys197Arg) is shown to disrupt LDLR activity (PMID: 25647241) Although not validated for clinical use, the in silico programs predict this variant to be damaging. Experimental studies are consistent with this variant resulting in a disruption of LDLR function (PMID 1301956). Based upon the above evidence, this c.590G>A (p.Cys197Tyr) variant in LDLR is classified as likely pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV001283997 SCV001469533 pathogenic not provided 2019-08-28 criteria provided, single submitter clinical testing Frequency data from large databases are of low quality and therefore uninformative. Found in at least one patient with expected phenotype for this gene. Predicted to have a damaging effect on the protein. Other pathogenic or likely pathogenic variants affect the same amino acid. Assessment of experimental evidence suggests this variant results in abnormal protein function. In multiple individuals, this variant has been seen with a single recessive pathogenic variant in the same gene, suggesting this variant may also be pathogenic.
Mayo Clinic Laboratories, Mayo Clinic RCV001283997 SCV001715239 pathogenic not provided 2019-05-20 criteria provided, single submitter clinical testing PS3_moderate, PS4, PM1, PM2, PM5, PP3
Institute of Human Genetics, University of Leipzig Medical Center RCV000237811 SCV001934462 pathogenic Familial hypercholesterolemia 1 2021-03-01 criteria provided, single submitter clinical testing
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde,Academisch Medisch Centrum RCV000237811 SCV000606165 pathogenic Familial hypercholesterolemia 1 no assertion criteria provided research
Clinical Genetics,Academic Medical Center RCV001283997 SCV001925904 likely pathogenic not provided no assertion criteria provided clinical testing

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