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

dbSNP: rs121908029

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
LDLR-LOVD, British Heart Foundation	RCV000237530	SCV000294906	likely pathogenic	Hypercholesterolemia, familial, 1	2016-03-25	criteria provided, single submitter	literature only
Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation	RCV000237530	SCV000540753	likely pathogenic	Hypercholesterolemia, familial, 1	2016-11-05	criteria provided, single submitter	clinical testing	Disrupt SDE motif. SDE bind structural Ca2+.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000781498	SCV000544665	pathogenic	Familial hypercholesterolemia	2024-12-25	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with glutamine, which is neutral and polar, at codon 228 of the LDLR protein (p.Glu228Gln). This variant is present in population databases (rs121908029, gnomAD 0.02%). This missense change has been observed in individual(s) with heterozygous familial hypercholesterolemia (PMID: 1301956, 8882879, 16250003, 17094996). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. Invitae Evidence Modeling of clinical and family history, age, sex, and reported ancestry of multiple individuals with this LDLR variant has been performed. This variant is expected to be pathogenic with a positive predictive value of at least 99%. This is a validated machine learning model that incorporates the clinical features of 363,995 individuals referred to our laboratory for LDLR testing. This variant is also known as p.Glu207Gln. ClinVar contains an entry for this variant (Variation ID: 251393). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt LDLR protein function with a positive predictive value of 95%. This variant disrupts the p.Glu228 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 1301956, 15359125, 18677035, 20736250). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille	RCV000237530	SCV000583725	pathogenic	Hypercholesterolemia, familial, 1	2017-03-30	criteria provided, single submitter	clinical testing
Laboratory of Genetics and Molecular Cardiology, University of São Paulo	RCV000237530	SCV000588512	likely pathogenic	Hypercholesterolemia, familial, 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	2024-04-27	criteria provided, single submitter	clinical testing	The LDLR c.682G>C (p.Glu228Gln) variant (also known as FH Tulsa-2 and E207Q) has been reported in the published literature in multiple individuals/families affected with hypercholesterolemia (PMIDs: 34037665 (2021), 32331935 (2020), 29720182 (2018), 25461735 (2015), 24507775 (2014), 17094996 (2007), 16389549 (2006), 16250003 (2005), 15199436 (2004), 8882879 (1996)). Experimental evidence indicates that this variant has a deleterious effect on LDLR protein function (PMIDs: 8784348 (1996), 1301956 (1992)). The frequency of this variant in the general population, 0.000196 (3/15314 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Based on the available information, this variant is classified as pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000781498	SCV001358759	pathogenic	Familial hypercholesterolemia	2019-12-31	criteria provided, single submitter	clinical testing	This missense variant (also known as p.Glu207Gln in the mature protein and as FH Tulsa-2) replaces glutamic acid with glutamine at codon 228 in the LDLR type A repeat 5 of the LDLR protein. The LDLR type A repeat 5 forms a Ca2+ binding pocket that is important for proper LDLR protein folding. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. This variant has been reported in heterozygosity in multiple individuals affected with familial hypercholesterolemia (PMID: 8882879, 12205127, 15199436, 16250003, 16389549, 17094996). This variant has also been reported in a child affected with severe hypercholesterolemia and cutaneous xanthomata, who was compound heterozygous for this variant and another pathogenic variant (PMID: 1301956, 8599353). LDLR activity was <5% in the cells obtained from this individual compound heterozygous individual (PMID: 1301956, 8599353). This variant has been identified in 4/247898 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different missense variant at the same position, p.Glu228Lys, is pathogenic (Clinvar variation ID: 3691), indicating that glutamic acid at this position is important for LDLR function. Based on the available evidence, this variant is classified as Pathogenic.
GeneDx	RCV000985770	SCV001781932	pathogenic	not provided	2022-06-17	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as FH Tulsa-2/Iraq and E207Q; This variant is associated with the following publications: (PMID: 15199436, 16389549, 31401775, 31491741, 32331935, 1301956, 24507775, 8882879, 17094996, 16250003, 31447099, 33740630, 34037665, 29720182, 8599353)
Ambry Genetics	RCV002365242	SCV002664966	pathogenic	Cardiovascular phenotype	2021-11-16	criteria provided, single submitter	clinical testing	The p.E228Q pathogenic mutation (also known as c.682G>C), located in coding exon 4 of the LDLR gene, results from a G to C substitution at nucleotide position 682. The glutamic acid at codon 228 is replaced by glutamine, an amino acid with highly similar properties, and is located in an SDE motif in the ligand binding domain. This alteration, historically described as p.E207Q, FH Tulsa-2, and FH Iraq, has been detected in numerous individuals with familial hypercholesterolemia (FH) across multiple ethnicities, with segregation reported in at least one first degree family member; at least two homozygous FH (HoFH) cases have been reported, both of whom had an additional LDLR variant detected (Hobbs HH et al. Hum. Mutat., 1992;1:445-66; Blackett PR et al. Am J Med Genet, 1995 Nov;59:300-3; Reshef A et al. Hum. Genet., 1996 Nov;98:581-6; Fouchier SW et al. Hum. Mutat., 2005 Dec;26:550-6; Jannes CE et al. Atherosclerosis, 2015 Jan;238:101-7; Paththinige CS et al. Lipids Health Dis, 2018 May;17:100; Tada H et al. J Clin Lipidol May-June 2020;14:346-351.e9). In addition, limited functional studies have suggested a reduction of LDLR activity to approximately 2-5% of wild-type (Hobbs HH et al. Hum. Mutat., 1992;1:445-66). In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
CeGaT Center for Human Genetics Tuebingen	RCV000985770	SCV004137806	pathogenic	not provided	2023-10-01	criteria provided, single submitter	clinical testing	LDLR: PS4, PM1, PM5, PP1, PS3:Supporting
Molecular Genetics, Royal Melbourne Hospital	RCV000237530	SCV004812568	pathogenic	Hypercholesterolemia, familial, 1	2023-03-30	criteria provided, single submitter	clinical testing	This sequence change in LDLR is predicted to replace glutamic acid with glutamine at codon 228, p.(Glu228Gln) (also known as FH Tulsa-2, FH Iraq, and p.Glu207Gln). The glutamic acid residue is highly conserved (100 vertebrates, UCSC), and is located in the LDL-receptor class A repeat 5 of the ligand-binding domain. Exon 4 (amino acids 105-232) where this variant is located, is defined as a mutational hotspot in LDLR. There is a small physicochemical difference between glutamic acid and glutamine. The highest population minor allele frequency in the population database gnomAD v3.1 is 0.01% (5/41,458 alleles) in the African/African American population, which is consistent with familial hypercholesterolaemia (FH). This is a recurrent variant that has been reported in multiple probands with FH and segregates with disease in at least one family (PMID: 25461735, 29720182, 32331935). This variant has been observed in trans with the variant c.663_683dup, p.(Asp221_Asp227dup) (PMID: 8599353) which is classified as pathogenic (ClinVar ID: 251358) in an individual with homozygous FH. Multiple lines of computational evidence predict a deleterious effect for the missense substitution (6/6 algorithms). Another missense variant c.682G>A, p.(Glu228Lys) in the same codon (with a similar physicochemical difference) has been classified as pathogenic for FH (ClinVar ID: 3691). Based on the classification scheme RMH Modified ACMG Guidelines v1.5.1, this variant is classified as PATHOGENIC. Following criteria are met: PM1, PM3, PM5, PS4_Supporting, PM2_Supporting, PP1, PP3.
Institute of Immunology and Genetics Kaiserslautern	RCV000237530	SCV005387823	pathogenic	Hypercholesterolemia, familial, 1	2022-08-02	criteria provided, single submitter	clinical testing	ACMG Criteria: PS3, PS4, PM2_P, PM5, PP3, PP4, PP5; Variant was found in heterozygous state.
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	RCV000237530	SCV000606202	pathogenic	Hypercholesterolemia, familial, 1		no assertion criteria provided	research
Natera, Inc.	RCV000781498	SCV002086383	pathogenic	Familial hypercholesterolemia	2021-07-07	no assertion criteria provided	clinical testing