Submissions for variant NM_000527.5(LDLR):c.1222G>A (p.Glu408Lys)

gnomAD frequency: 0.00001  dbSNP: rs137943601

Total submissions: 22

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	RCV000030125	SCV001960925	likely pathogenic	Hypercholesterolemia, familial, 1	2021-06-09	reviewed by expert panel	curation	NM_000527.5(LDLR):c.1222G>A (p.Glu408Lys) variant is classified as Likely pathogenic for Familial Hypercholesterolemia by applying evidence codes (PM2, PS3_Moderate, PS4_Moderate, PP1, PP3 and PP4) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755). The supporting evidence is as follows: PM2 - PopMax MAF = 0.00001763 (0.0018%) in European non-Finnish exomes (gnomAD v2.1.1). PS3_moderate - Level 2 assay: PMID:1301956 - study on hmz patient's fibroblasts, 125I-LDL assay, effect value reported as <2%; Level 2 assay: PMID: 9026534 - Epstein-Barr virus-transformed lymphoblasts from hmz patient, 125I-LDL assays - Results - 5-10% LDLR activity. PS4_moderate - Variant meets PM2. Variant identified in 8 index cases (1 case from Center of molecular biology and gene therapy with Simon-Broome criteria; 1 case from GeneDx laboratory with Simon Broome criteria, 1 case from Color laboratory with Simon Broome criteria, 1 case from Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA) with Simon Broome criteria, 1 case from University of British Columbia with DLCN criteria, 1 case from Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge with Simon-Broome criteria, 2 cases from Ambry Genetics with Simon-Broome criteria). PP1 - Variant segregates with phenotype in 2 members of family (2 meiosis) from Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge. PP3 - REVEL: 0,879. Score is above 0,75. PP4 - Variant meets PM2. Variant identified in 8 index cases (see PS4_Moderate).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001034664	SCV000052780	pathogenic	Familial hypercholesterolemia	2019-09-16	criteria provided, single submitter	clinical testing	Variant summary: LDLR c.1222G>A (p.Glu408Lys) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251304 control chromosomes (gnomAD). The variant, c.1222G>A, has been reported in the literature in individuals affected with Familial Hypercholesterolemia (Hobbs_1992, Webb_1996). These data indicate that the variant is very likely to be associated with disease. At least two publications report experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity (Hobbs_1992, Webb_1996). Eight ClinVar submissions (evaluation after 2014) cite the variant twice as pathogenic and six times as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001034664	SCV000285013	pathogenic	Familial hypercholesterolemia	2024-01-22	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 408 of the LDLR protein (p.Glu408Lys). This variant is present in population databases (rs137943601, gnomAD 0.002%). This missense change has been observed in individuals with hypercholesterolemia (PMID: 1301956, 14974088, 17347910, 19843101, 20236128). This variant is also known as FH Algeria-1 or E387K. ClinVar contains an entry for this variant (Variation ID: 36453). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt LDLR protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects LDLR function (PMID: 1301956, 21531209). For these reasons, this variant has been classified as Pathogenic.
LDLR-LOVD, British Heart Foundation	RCV000030125	SCV000295310	likely pathogenic	Hypercholesterolemia, familial, 1	2016-03-25	criteria provided, single submitter	literature only
Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge	RCV000030125	SCV000322938	likely pathogenic	Hypercholesterolemia, familial, 1	2016-03-01	criteria provided, single submitter	research	0/208 non-FH alleles
Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix	RCV000030125	SCV000503319	likely pathogenic	Hypercholesterolemia, familial, 1	2016-12-16	criteria provided, single submitter	clinical testing	subjects mutated among 2600 FH index cases screened = 10 , family members = 5 with co-segregation / FH-Algérie-1/Osaka, <2% LDLR Activity / Software predictions: Conflicting
Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation	RCV000030125	SCV000540803	likely pathogenic	Hypercholesterolemia, familial, 1	2016-11-05	criteria provided, single submitter	clinical testing
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille	RCV000030125	SCV000583809	pathogenic	Hypercholesterolemia, familial, 1	2017-03-30	criteria provided, single submitter	clinical testing
Fundacion Hipercolesterolemia Familiar	RCV000030125	SCV000607577	likely pathogenic	Hypercholesterolemia, familial, 1	2016-03-01	criteria provided, single submitter	research
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000844747	SCV000711398	likely pathogenic	Homozygous familial hypercholesterolemia	2021-03-22	criteria provided, single submitter	clinical testing	proposed classification - variant undergoing re-assessment, contact laboratory
Color Diagnostics, LLC DBA Color Health	RCV001034664	SCV001347901	pathogenic	Familial hypercholesterolemia	2023-03-08	criteria provided, single submitter	clinical testing	This missense variant (also known as p.Glu387Lys in the mature protein and as FH-Algeria-1) replaces glutamic acid with lysine at codon 408 in the EGF precursor homology domain of the LDLR protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown that this variant causes a significant decrease in LDLR function due to impaired LDLR recycling and increased protein degradation in lysosomes (PMID: 9026534, 1301956, 19026292, 2153120). This variant has been reported in many unrelated individuals affected with familial hypercholesterolemia (PMID: 1301956, 9026534, 9698020, 12436241, 14974088, 15199436, 16250003, 17094996, 17347910, 17765246, 18022922, 19843101, 22698793, 29353225, 29396260, 30415195). This variant has also been reported in two unrelated individuals affected with homozygous familial hypercholesterolemia (PMID: 9026534, 19026292). This variant has been identified in 2/251104 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.
Institute of Human Genetics, University of Leipzig Medical Center	RCV000030125	SCV001429020	pathogenic	Hypercholesterolemia, familial, 1	2019-07-23	criteria provided, single submitter	clinical testing
Brunham Lab, Centre for Heart and Lung Innovation, University of British Columbia	RCV000030125	SCV001432552	likely pathogenic	Hypercholesterolemia, familial, 1	2018-11-29	criteria provided, single submitter	research
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	RCV001034664	SCV001435008	pathogenic	Familial hypercholesterolemia	2019-06-17	criteria provided, single submitter	clinical testing	This c.1222G>A (p.Glu408Lys) variant in the LDLR gene has been reported in multiple unrelated individuals affected with familial hypercholesteromeia (PMID 1301956, 9026534, 16250003, 17347910, 21531209) and myocardial infarction (PMID 25487149). LDL-R activity in cells derived from affected individuals was under 10% compared to wildtype (PMID 1301956, 9026534). This variant is extremely rare in general population databases. Multiple lines of algorithms predicted this p.Glu408Lys change to be deleterious. Therefore, this c.1222G>A (p.Glu408Lys) variant in the LDLR gene is classified pathogenic.
GeneDx	RCV001537253	SCV001754112	pathogenic	not provided	2024-10-23	criteria provided, single submitter	clinical testing	Observed in the heterozygous, compound heterozygous, and homozygous state in multiple unrelated individuals from different ethnic backgrounds with FH in published literature (PMID: 1301956, 9026534, 9698020, 10882754, 12436241, 14974088, 15199436, 16250003, 17094996, 17765246, 19318025, 22698793, 22883975, 29353225, 30592178, 33418990); Also known as FH Algeria-1, FH Osaka, and p.E387K due to alternate nomenclature; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 9698020, 10882754, 29396260, 29874871, 32759540, 25637381, 25487149, 1301956, 9026534, 15199436, 14974088, 12436241, 16250003, 17094996, 17539906, 17765246, 18700895, 20236128, 19837725, 22698793, 19318025, 22883975, 25911074, 29261184, 29353225, 32163632, 31447099, 33740630, 34037665, 30592178, 33418990, 32719484, 37589137, 37409534, 37128917, 36648309, 33955087, 33994402, 19280064)
Ambry Genetics	RCV002362601	SCV002658943	pathogenic	Cardiovascular phenotype	2022-03-07	criteria provided, single submitter	clinical testing	The p.E408K pathogenic mutation (also known as c.1222G>A), located in coding exon 9 of the LDLR gene, results from a G to A substitution at nucleotide position 1222. The glutamic acid at codon 408 is replaced by lysine, an amino acid with similar properties. This alteration (also referred to as p.E387K) has been reported in multiple unrelated individuals with heterozygous or homozygous familial hypercholesterolemia (FH), has been detected in FH cohorts, and has shown some segregation with disease in families (Hobbs HH et al. Hum. Mutat. 1992;1:445-66; Webb JC et al. J. Lipid Res. 1996;37:368-81; Fouchier SW et al. Hum Mutat. 2005 Dec;26(6):550-6; Tich&yacute; L et al. Atherosclerosis. 2012;223:401-8; Chan ML et al. Mol Genet Genomic Med. 2019 02;7(2):e00520; Galiano M et al. J Clin Apher. 2020 Jun;35(3):163-171; Meshkov A et al. Genes (Basel). 2021 01;12(1)). Functional studies indicate that this alteration results in deficient protein function (Hobbs HH et al., 1992; Webb JC et al. 1996; Str&oslash;m TB et al. Biochem. Biophys. Res. Commun. 2011;408:642-6). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Fulgent Genetics, Fulgent Genetics	RCV000030125	SCV002789095	pathogenic	Hypercholesterolemia, familial, 1	2021-08-12	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001537253	SCV004219939	pathogenic	not provided	2023-01-16	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.000008 (2/251104 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in several individuals with Familial Hypercholesterolemia (FH) (PMID: 1301956 (1992), 9026534 (1996), 12436241 (2002), 14974088 (2004), 15199436 (2004), 17347910 (2007)), and has been found to segregate with disease in family members (PMID: 32163632 (2020)). Functional studies have reported this variant has a damaging effect on LDLR activity (PMID: 1301956 (1992)), 9026534 (1996)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, this variant is classified as pathogenic.
All of Us Research Program, National Institutes of Health	RCV000030125	SCV004820280	pathogenic	Hypercholesterolemia, familial, 1	2023-04-28	criteria provided, single submitter	clinical testing	This missense variant (also known as p.Glu387Lys in the mature protein and as FH-Algeria-1) replaces glutamic acid with lysine at codon 408 in the EGF precursor homology domain of the LDLR protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown that this variant causes a significant decrease in LDLR function due to impaired LDLR recycling and increased protein degradation in lysosomes (PMID: 9026534, 1301956, 19026292, 2153120). This variant has been reported in many unrelated individuals affected with familial hypercholesterolemia (PMID: 1301956, 9026534, 9698020, 12436241, 14974088, 15199436, 16250003, 17094996, 17347910, 17765246, 18022922, 19843101, 22698793, 29353225, 29396260, 30415195). This variant has also been reported in two unrelated individuals affected with homozygous familial hypercholesterolemia (PMID: 9026534, 19026292). This variant has been identified in 2/251104 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.
CSER _CC_NCGL, University of Washington	RCV002051647	SCV000190277	likely benign	Hypercholesterolemia	2014-06-01	no assertion criteria provided	research
Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital	RCV000030125	SCV000268606	pathogenic	Hypercholesterolemia, familial, 1	2011-08-25	no assertion criteria provided	clinical testing
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	RCV000030125	SCV000606366	pathogenic	Hypercholesterolemia, familial, 1		no assertion criteria provided	research