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

Total submissions: 10

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