ClinVar Miner

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

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Total submissions: 11
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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
Integrated Genetics/Laboratory Corporation of America 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 2019-12-30 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 RCV000589041 SCV001358756 pathogenic Familial hypercholesterolemia 2020-02-25 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

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