ClinVar Miner

Submissions for variant NM_000527.4(LDLR):c.682G>C (p.Glu228Gln) (rs121908029)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Integrated Genetics/Laboratory Corporation of America RCV000781498 SCV000919578 pathogenic Familial hypercholesterolemias 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.
Invitae RCV000781498 SCV000544665 pathogenic Familial hypercholesterolemias 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.
LDLR-LOVD, British Heart Foundation RCV000237530 SCV000294906 likely pathogenic Familial hypercholesterolemia 2016-03-25 criteria provided, single submitter literature only
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde,Academisch Medisch Centrum RCV000237530 SCV000606202 pathogenic Familial hypercholesterolemia no assertion criteria provided research
Laboratory of Genetics and Molecular Cardiology,University of São Paulo RCV000237530 SCV000588512 likely pathogenic Familial hypercholesterolemia 2016-03-01 criteria provided, single submitter research
Molecular Genetics Laboratory,Centre for Cardiovascular Surgery and Transplantation RCV000237530 SCV000540753 likely pathogenic Familial hypercholesterolemia 2016-11-05 criteria provided, single submitter clinical testing Disrupt SDE motif. SDE bind structural Ca2+.
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille RCV000237530 SCV000583725 pathogenic Familial hypercholesterolemia 2017-03-30 criteria provided, single submitter clinical testing

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