ClinVar Miner

Submissions for variant NM_000527.4(LDLR):c.589T>G (p.Cys197Gly) (rs730882085)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
LDLR-LOVD, British Heart Foundation RCV000237260 SCV000294805 likely pathogenic Familial hypercholesterolemia 1 2016-03-25 criteria provided, single submitter literature only
Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies,APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix RCV000237260 SCV000503183 likely pathogenic Familial hypercholesterolemia 1 2016-12-16 criteria provided, single submitter clinical testing subject mutated among 2600 FH index cases screened = 1, family member=1 / Software predictions: Damaging
GeneDx RCV000490241 SCV000576754 pathogenic not provided 2017-04-20 criteria provided, single submitter clinical testing The C197G pathogenic variant in the LDLR gene has been previously reported in a heterozygous French individual with familial hypercholesterolemia (Marduel et al., 2010). It has also been reported in a compound heterozygous Caucasian individual, who also harbored an intragenic deletion of exons 4-18 in the LDLR gene, and who had a history of childhood-onset coronary artery disease, severe hypercholesterolemia, and no LDLR activity detected in fibroblast cultures (Stein et al., 2013). Additionally, this variant is classified as likely pathogenic in ClinVar by a different clinical laboratory in association with familial hypercholesterolemia (ClinVar SCV000503183.1; Landrum et al., 2016). The C197G variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved in mammals and in silico analysis predicts this variant is probably damaging to the protein structure/function. Moreover, C197G abolishes the C197-C209 disulfide bond within the LDL-receptor class A5 domain, which is one of seven class A repeat domains in the N-terminal region of the LDL-receptor protein responsible for LDL binding. Furthermore, pathogenic missense variants in the same residue (C197R, C197F, C197Y) have been previously reported in association with familial hypercholesterolemia (Webb et al., 1996; Hobbs et al., 1992), further supporting the functional importance of this residue. Finally, the C197G variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server).
Invitae RCV000775044 SCV000830690 pathogenic Familial hypercholesterolemia 2018-07-26 criteria provided, single submitter clinical testing This sequence change replaces cysteine with glycine at codon 197 of the LDLR protein (p.Cys197Gly). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and glycine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in several individuals affected with familial hypercholesterolemia (PMID: 20809525, 24014831). ClinVar contains an entry for this variant (Variation ID: 251308). 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). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. A different missense substitution at this codon (p.Cys197Tyr) has been determined to be pathogenic (PMID: 1301956, 27816806, 23064986, 18096825, 21276076, 20538126, 27765764). 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.
Color RCV000775044 SCV000909141 pathogenic Familial hypercholesterolemia 2018-08-21 criteria provided, single submitter clinical testing Pathogenic variant based on current evidence: This missense variant (also known as p.Cys176Gly in the mature protein) is located in the fifth LDLR type A repeat of the 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. Experimental functional study has shown no detectable LDLR activity in cells from an individual compound heterozygous for this variant and deletion of exons 4-18 (PMID: 24014831). Computational splicing tools suggest that this variant may not impact the RNA splicing. While this variant is rare in the general population (0/277264 chromosomes in the Genome Aggregation Database), it has been reported in multiple individuals affected with familial hypercholesterolemia (PMID: 20809525, 24014831, 28964736). In addition, different variants occurring in the same amino acid position (p.Cys197Arg, p.Cys197Phe and p.Cys197Tyr) are considered deleterious (Clinvar). Based on available evidence, this variant is classified as Pathogenic.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000825594 SCV000966936 likely pathogenic Familial hypercholesterolemia - homozygous 2018-07-18 criteria provided, single submitter clinical testing The p.Cys197Gly variant in LDLR has been reported in at least 3 individuals wit h hypercholesterolemia (FH), one of which was compound heterozygous (with a dele tion of exons 4-18) and had homozygous familial hypercholesterolemia (Marduel 2 010, Stein 2013, Defesche 2017, ClinVar: Variation ID 251308). This variant was absent from large population studies. Functional studies provide some evidence that the p.Cys197Gly variant may impact protein function (Stein 2013). However, these types of assays may not accurately represent biological function. Computat ional prediction tools and conservation analysis suggest that the p.Cys197Gly va riant may impact the protein, though this information is not predictive enough t o determine pathogenicity. Finally, other variants at this position (Cys197Arg, Cys197Tyr, Cys197Phe, Cys197Trp) have been reported in individuals with FH (Clin var, HGMD database), suggesting that changes at this position are not tolerated. In summary, although additional studies are required to fully establish its cli nical significance, the p.Cys197Gly variant is likely pathogenic. ACMG/AMP Crite ria applied: PM2; PM3; PP3; PS3_Supporting; PS4_Supporting.
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde,Academisch Medisch Centrum RCV000237260 SCV000606164 pathogenic Familial hypercholesterolemia 1 no assertion criteria provided research

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