Submissions for variant NM_000527.5(LDLR):c.589T>G (p.Cys197Gly)

dbSNP: rs730882085

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
LDLR-LOVD, British Heart Foundation	RCV000237260	SCV000294805	likely pathogenic	Hypercholesterolemia, familial, 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	Hypercholesterolemia, familial, 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	2023-02-10	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Reported in ClinVar as pathogenic or likely pathogenic (ClinVar Variant ID#251308; ClinVar); Not observed at significant frequency in large population cohorts (gnomAD); Also denoted as C176G due to alternate nomenclature; This variant is associated with the following publications: (PMID: 31447099, 28964736, 32143996, 20809525, 34037665, 26582918, 24014831, 27535533, 2988123, 12459547, 9026534, 1301956, 18096825, 20538126, 21276076, 23064986, 27765764, 27816806, 30293936, 33740630, 33994402)
Invitae	RCV000775044	SCV000830690	pathogenic	Familial hypercholesterolemia	2023-07-19	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Cys197 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been observed in individuals with LDLR-related conditions (PMID: 1301956, 18096825, 20145306, 20538126, 20809525, 21276076, 23064986, 24014831, 27765764, 27816806), which suggests that this may be a clinically significant amino acid residue. 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). 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. ClinVar contains an entry for this variant (Variation ID: 251308). This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 20809525, 24014831). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces cysteine, which is neutral and slightly polar, with glycine, which is neutral and non-polar, at codon 197 of the LDLR protein (p.Cys197Gly).
Color Diagnostics, LLC DBA Color Health	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, Mass General Brigham Personalized Medicine	RCV000825594	SCV000966936	likely pathogenic	Homozygous familial hypercholesterolemia	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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000490241	SCV001469532	likely pathogenic	not provided	2019-09-09	criteria provided, single submitter	clinical testing	Not found in the total gnomAD dataset, and the data is high quality. Found in at least one patient with expected phenotype for this gene. Predicted to have a damaging effect on the protein. Located in potentially critical domain of 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.
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV000237260	SCV002499138	pathogenic	Hypercholesterolemia, familial, 1	2022-03-18	criteria provided, single submitter	clinical testing	PS4, PM1, PM2, PM5, PP3
Ambry Genetics	RCV002356329	SCV002652557	pathogenic	Cardiovascular phenotype	2021-01-29	criteria provided, single submitter	clinical testing	The p.C197G pathogenic mutation (also known as c.589T>G), located in coding exon 4 of the LDLR gene, results from a T to G substitution at nucleotide position 589. The cysteine at codon 197, located in LDLR class A repeat 5, is replaced by glycine, an amino acid with highly dissimilar properties. Pathogenic LDLR mutations that result in the substitution or generation of cysteine residues within the cysteine-rich LDLR class A repeats and EGF-like domains are common in familial hypercholesterolemia (FH) (Villéger L. Hum Mutat. 2002;20(2):81-7). This alteration has been reported in individuals with FH (Marduel M et al. Hum. Mutat., 2010 Nov;31:E1811-24; Stein EA et al. Circulation, 2013 Nov;128:2113-20; Defesche JC et al. J Clin Lipidol Sep;11:1338-1346.e7). Internal structural analysis indicates this alteration eliminates a disulfide bond critical for the structural integrity of LDLR class A repeat 5. In addition, alterations affecting the same amino acid (C197Y, C197W, C197F, C197R) have also been described in FH (Hobbs HH et al. Hum. Mutat., 1992;1:445-66; Chmara M et al. J Appl Genet. 2010;51(1):95-106; Webb JC et al. J. Lipid Res., 1996 Feb;37:368-81). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	RCV000237260	SCV000606164	pathogenic	Hypercholesterolemia, familial, 1		no assertion criteria provided	research