ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.682G>C (p.Glu228Gln)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
LDLR-LOVD, British Heart Foundation RCV000237530 SCV000294906 likely pathogenic Familial hypercholesterolemia 1 2016-03-25 criteria provided, single submitter literature only
Molecular Genetics Laboratory,Centre for Cardiovascular Surgery and Transplantation RCV000237530 SCV000540753 likely pathogenic Familial hypercholesterolemia 1 2016-11-05 criteria provided, single submitter clinical testing Disrupt SDE motif. SDE bind structural Ca2+.
Invitae RCV000781498 SCV000544665 pathogenic Familial hypercholesterolemia 2018-08-02 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with glutamine at codon 228 of the LDLR protein (p.Glu228Gln). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and glutamine. This variant is present in population databases (rs121908029, ExAC 0.002%). This variant has been reported in several individuals affected with heterozygous familial hypercholesterolemia (PMID: 8882879, 16250003, 17094996), and one individual with homozygous familial hypercholesterolemia (PMID: 1301956). This variant is also known as p.Glu207Gln in the literature and Tulsa-2. ClinVar contains an entry for this variant (Variation ID: 251393). 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. A different missense substitution at this codon (p.Glu228Lys) is reported to be deleterious (PMID: 1301956, 15359125, 18677035, 20736250). This variant is also known as p.Glu207Lys in the literature. This indicates that the glycine residue is important for LDLR protein function. For these reasons, this variant has been classified as Pathogenic.
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille RCV000237530 SCV000583725 pathogenic Familial hypercholesterolemia 1 2017-03-30 criteria provided, single submitter clinical testing
Laboratory of Genetics and Molecular Cardiology, University of São Paulo RCV000237530 SCV000588512 likely pathogenic Familial hypercholesterolemia 1 2016-03-01 criteria provided, single submitter research
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000781498 SCV000919578 pathogenic Familial hypercholesterolemia 2017-10-12 criteria provided, single submitter clinical testing Variant summary: The LDLR c.682G>C (p.Glu228Gln) variant involves the alteration of a conserved nucleotide. 4/5 in silico tools predict a damaging outcome for this variant. This variant was found in 4/244590 control chromosomes at a frequency of 0.0000164, which does not exceed the estimated maximal expected allele frequency of a pathogenic LDLR variant (0.0012508). The variant has been reported in numerous affected individuals in the literature and has been reported twice was observed in patients with <5% LDLR activity who carried a second LDLR variant (Hobbs_1992, Blackett_1995). Other variants at the same residue (p.E228K, p.E228A and p.E228*) have also been reported in the literature and databases in association with hypercholesterolaemia, suggesting the residue p.Glu228 could represent mutation hot-spot. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as likely pathogenic/pathogenic. Taken together, this variant is classified as pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000985770 SCV001134268 pathogenic not provided 2018-10-10 criteria provided, single submitter clinical testing The best available variant frequency is uninformative. Statistically enriched in patients compared to ethnically matched controls. Predicted to have a damaging effect on the protein. Assessment of experimental evidence suggests this variant results in abnormal protein function.
Color Health, Inc RCV000781498 SCV001358759 pathogenic Familial hypercholesterolemia 2019-12-31 criteria provided, single submitter clinical testing
GeneDx RCV000985770 SCV001781932 pathogenic not provided 2021-08-13 criteria provided, single submitter clinical testing Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Disrupts a negatively charged triplet, Ser-Asp-Glu, located at the carboxyl-terminal end of the LDL-receptor class A5 repeat domain that is critical for ligand binding (Schneider et al., 2003); Reported in ClinVar as pathogenic and likely pathogenic (ClinVar Variant ID# 251393; Landrum et al., 2016); Also known as FH Tulsa-2 and E207Q; This variant is associated with the following publications: (PMID: 31447099, 32331935, 31491741, 31401775, 16389549, 8599353, 29720182, 15199436, 16250003, 17094996, 8882879, 24507775, 1301956)
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde,Academisch Medisch Centrum RCV000237530 SCV000606202 pathogenic Familial hypercholesterolemia 1 no assertion criteria provided research

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