Submissions for variant NM_000527.5(LDLR):c.301G>A (p.Glu101Lys) (rs144172724)

Total submissions: 18

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000775032	SCV000285028	pathogenic	Familial hypercholesterolemia	2019-09-29	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid with lysine at codon 101 of the LDLR protein (p.Glu101Lys). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is present in population databases (rs144172724, ExAC <0.01%). This variant has been reported in the literature to segregate with disease in two families (PMID: 1301940, 1352322) and also present in multiple individuals affected with hypercholesterolemia (PMID: 1352322, 11668627, 23669246, 18718593, 19843101, 15241806, 20236128, 17142622, 16314194, 11668640). This variant is also known in the literature as E80K. ClinVar contains an entry for this variant (Variation ID: 161266). One experimental study has shown that this missense variant inhibited LDL uptake in Hel-Kyoto cells (PMID: 25647241). In summary, this variant is present at a very low frequency in the general population, has been reported to segregate with disease and is present in multiple individuals with hypercholesterolemia, and has been shown to affected protein function in vitro. For these reasons, it has been classified as Pathogenic.
LDLR-LOVD, British Heart Foundation	RCV000211583	SCV000294591	likely pathogenic	Familial hypercholesterolemia 1	2016-03-25	criteria provided, single submitter	literature only
Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge	RCV000211583	SCV000322886	likely pathogenic	Familial hypercholesterolemia 1	2016-03-01	criteria provided, single submitter	research	0/208 non-FH alleles; 0/100 healthy control individuals; 0/60 healthy control individuals
Robarts Research Institute,Western University	RCV000211583	SCV000484724	likely pathogenic	Familial hypercholesterolemia 1		criteria provided, single submitter	clinical testing
Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies,APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix	RCV000211583	SCV000503127	likely pathogenic	Familial hypercholesterolemia 1	2016-12-16	criteria provided, single submitter	clinical testing	subjects mutated among 2600 FH index cases screened = 8 , family members = 12 with co-segregation / FH-Lancashire
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille	RCV000211583	SCV000583649	pathogenic	Familial hypercholesterolemia 1	2017-03-30	criteria provided, single submitter	clinical testing
Fundacion Hipercolesterolemia Familiar	RCV000211583	SCV000607441	likely pathogenic	Familial hypercholesterolemia 1	2016-03-01	criteria provided, single submitter	research
GeneDx	RCV000162016	SCV000617500	pathogenic	not provided	2017-09-07	criteria provided, single submitter	clinical testing	The E101K (aka E80K, FH Lancashire) pathogenic variant is part of a negatively charged triplet, Ser-Asp-Glu, located at the carboxyl-terminal end of the LDL-receptor A2 repeat domain in the LDLR gene, and is critical for ligand binding (Schneider et al., 2003). E101K has been published numerous times in unrelated patients from different ethnic backgrounds with FH (Webb et al., 1992; Wang et al., 2001; Mozas et al., 2004; Robles-Osorio et al., 2006; Humphries et al., 2006; Al-Khateeb et al., 201; Futema et al., 2013). Patient protein studies and in vitro analysis support alteration to protein processing and intracellular transport, in the presence of E101K (Webb et al., 1992; Thormaehlen et al., 2015). E101K results in a non-conservative amino acid substitution at a position that is conserved across species. Additionally, this variant is classified as pathogenic/likely pathogenic and reported to segregate with disease by other clinical laboratories in ClinVar (ClinVar SCV000285028.2, SCV000484724.1, SCV000503127.1, SCV000583649.1, SCV000268550.1, ; Landrum et al., 2016). Furthermore, the E101K variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server).
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine	RCV000844744	SCV000711395	pathogenic	Homozygous familial hypercholesterolemia	2019-03-03	criteria provided, single submitter	clinical testing	The p.Glu101Lys variant in LDLR has been reported in the heterozygous state in >30 individuals with familial hypercholesterolemia (FH), in the compound heterozygous state in 1 individual with homozygous FH (Loux 1992, Webb 1992, García-García 2001, Mozas 2004, Humphries 2006, Miyakem2009, Taylor 2010, Futema 2013, Do 2015) and segregated with disease in four affected relatives from two families (Webb 1992, Loux 1992). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID# 161266). In vitro functional studies provide some evidence that the p.Glu101Lys variant may impact protein function (Webb 1992). This variant has also been identified in 3/111700 European chromosomes by the genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org). This frequency is low enough to be consistent with the frequency of FH in the general population. Computational prediction tools and conservation analysis suggests that the p.Glu101Lys variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, this variant meets criteria to be classified as pathogenic for familial hypercholesterolemia in an autosomal dominant manner based upon presence in multiple affected individuals, segregation studies, low frequency in the general population and functional evidence. The ACMG/AMP Criteria applied: PS4, PM2, PS3_Moderate, PP1, PP3.
Iberoamerican FH Network	RCV000211583	SCV000748036	likely pathogenic	Familial hypercholesterolemia 1	2016-03-01	criteria provided, single submitter	research
Fulgent Genetics,Fulgent Genetics	RCV000211583	SCV000894165	pathogenic	Familial hypercholesterolemia 1	2018-10-31	criteria provided, single submitter	clinical testing
Color	RCV000775032	SCV000909129	pathogenic	Familial hypercholesterolemia	2017-07-25	criteria provided, single submitter	clinical testing	Pathogenic variant based on current evidence: This missense variant (also known as p.Glu80Lys in the mature protein) is located in the LDLR type A repeat 2 of the ligand binding domain of the LDLR protein. Computational prediction tools and conservation analyses suggest that this variant may have deleterious impact on the protein function. Computational splicing tools suggest that this variant may not impact the RNA splicing. Experimental studies have shown that this variant significantly inhibits LDL uptake (PMID: 25647241). This variant has been reported in more than 10 individuals affected with hypercholesterolemia (PMID: 1352322, 11668627, 23669246, 18718593, 19843101, 15241806, 20236128, 17142622, 16314194, 11668640) and reported to segregate with disease in two families (PMID: 1301940 and 1352322). This variant is rare in the general population and has been identified in 4/246246 chromosomes by the Genome Aggregation Database (gnomAD). Based on available evidence, this variant is classified as Pathogenic.
Integrated Genetics/Laboratory Corporation of America	RCV000775032	SCV000919570	pathogenic	Familial hypercholesterolemia	2018-01-19	criteria provided, single submitter	clinical testing	Variant summary: The LDLR c.301G>A (p.Glu101Lys) variant involves the alteration of a conserved nucleotide located in the low-density lipoprotein (LDL) receptor class A repeat (InterPro) and 4/5 in silico tools predict a damaging outcome for this variant. One functional study, Thormaehlen_2015, found this variant to be associated with pronouncedly inhibited LDL-uptake in cells." This variant was found in 4/263560 control chromosomes (gnomAD and publication controls) at a frequency of 0.0000152, which does not exceed the estimated maximal expected allele frequency of a pathogenic LDLR variant (0.0012508). This variant was found in multiple unrelated patients with FH (Al-Khateeb_2011, Khera_2016, Futema_2013). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Brunham Lab, Centre for Heart and Lung Innovation,University of British Columbia	RCV000211583	SCV001432643	pathogenic	Familial hypercholesterolemia 1	2019-05-23	criteria provided, single submitter	research
Dept. of Genetics and Pharmacogenomics, Merck Research Labs	RCV000162016	SCV000189619	not provided	not provided		no assertion provided	in vitro
CSER _CC_NCGL, University of Washington	RCV000148571	SCV000190284	likely pathogenic	Hypercholesterolaemia	2014-06-01	no assertion criteria provided	research
Cardiovascular Genetics Laboratory,PathWest Laboratory Medicine WA - Fiona Stanley Hospital	RCV000211583	SCV000268550	pathogenic	Familial hypercholesterolemia 1	2008-06-05	no assertion criteria provided	clinical testing
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde,Academisch Medisch Centrum	RCV000211583	SCV000606069	pathogenic	Familial hypercholesterolemia 1		no assertion criteria provided	research