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

gnomAD frequency: 0.00001  dbSNP: rs144172724

Total submissions: 26

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	RCV000211583	SCV002506353	pathogenic	Hypercholesterolemia, familial, 1	2021-12-13	reviewed by expert panel	curation	The NM_000527.5(LDLR):c.301G>A (p.Glu101Lys) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying evidence codes (PP1_Strong, PS4, PM2, PM3, PS3_Moderate, 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: PP1_strong - variant segregates with the FH phenotype in at least 19 relatives with the variant and LDL-C above the 75th percentile from several labs (Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, Ambry, Robarts Research Institute), so PP1_Strong is met. PS4 - variant meets PM2 and is identified in at least 16 index cases who fulfill validated clinical criteria for FH from several labs (SB criteria from Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge and DLCN >=6 from Color, Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA) and Robarts Research Institute), so PS4 is met. PM2 - PopMax MAF = 0.00003266 (0.003%) in south asian exomes (gnomAD v2.1.1). It is below 0.02%, so PM2 is met. PM3 - variant meets PM2 and was identified in 1 index case with LDL 16.2 mmol/L and also LDLR exon 15 deletion from Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA) - Likely pathogenic by these guidelines, so PM3 is met PS3_moderate - Level 2 FS: Hobbs et al., 1992 (PMID 1301956): Hmz patient fibroblast, 125I-LDL assays - results: 15-30% LDLR activity. Activity is below 70% of wild-type, so PS3_Moderate is met. PP3 - REVEL = 0.896. It is above 0.75, so PP3 is met. PP4 - variant meets PM2 and is identified in at least 1 index case who fulfills SB criteria from Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge. so, PP4 is met
Invitae	RCV000775032	SCV000285028	pathogenic	Familial hypercholesterolemia	2024-01-11	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 101 of the LDLR protein (p.Glu101Lys). This variant is present in population databases (rs144172724, gnomAD 0.003%). This missense change has been observed in individuals with hypercholesterolemia (PMID: 1301940, 1352322, 11668627, 11668640, 15241806, 16314194, 17142622, 18718593, 19843101, 20236128, 23669246). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 161266). 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: 25647241). For these reasons, this variant has been classified as Pathogenic.
LDLR-LOVD, British Heart Foundation	RCV000211583	SCV000294591	likely pathogenic	Hypercholesterolemia, familial, 1	2016-03-25	criteria provided, single submitter	literature only
Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge	RCV000211583	SCV000322886	likely pathogenic	Hypercholesterolemia, familial, 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	Hypercholesterolemia, familial, 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	Hypercholesterolemia, familial, 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	Hypercholesterolemia, familial, 1	2017-03-30	criteria provided, single submitter	clinical testing
Fundacion Hipercolesterolemia Familiar	RCV000211583	SCV000607441	likely pathogenic	Hypercholesterolemia, familial, 1	2016-03-01	criteria provided, single submitter	research
GeneDx	RCV000162016	SCV000617500	pathogenic	not provided	2022-08-22	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; Patient protein studies and in vitro analysis support decreased receptor activity, alteration to protein processing, and intracellular transport (Hobbs et al., 1992; Webb et al., 1992; Thormaehlen et al., 2015); Reported in ClinVar as a pathogenic variant by the ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel; Also known as p.E80K; This variant is associated with the following publications: (PMID: 11668640, 32759540, 9676383, 34662886, 25637381, 25487149, 1301940, 25647241, 1352322, 16314194, 21418584, 15241806, 22883975, 20236128, 18718593, 15523646, 11668627, 23669246, 17142622, 24507775, 1301956, 31491741, 31447099, 31345425, 32041611, 33303402, 32331935, 9547893, 33740630, 34037665, 33087929, 27535533)
Laboratory for Molecular Medicine, Mass General Brigham 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	Hypercholesterolemia, familial, 1	2016-03-01	criteria provided, single submitter	research
Fulgent Genetics, Fulgent Genetics	RCV000211583	SCV000894165	pathogenic	Hypercholesterolemia, familial, 1	2021-11-20	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000775032	SCV000909129	pathogenic	Familial hypercholesterolemia	2023-10-25	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with lysine at codon 101 in the LDLR type A repeat 2 of the ligand binding domain of the LDLR protein. This variant is also known as p.Glu80Lys in the mature protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Experimental studies have shown that this variant significantly inhibits LDL uptake (PMID: 25647241). This LDLR variant has been reported in over 20 heterozygous individuals affected with familial hypercholesterolemia (PMID: 1301940, 1352322, 11668627, 11668640, 15241806, 16314194, 17142622, 18718593, 19843101, 20236128, 23669246, 31345425, 32331935, 33740630, 34037665, 36499307; Color internal data). This variant has also been observed in compound heterozygous state with a known pathogenic LDLR variant in two individuals affected with severe homozygous familial hypercholesterolemia, a phenotype expected of having two deleterious LDLR variants (PMID: 1352322, 37119068). It has been shown that this variant segregates with disease in multiple affected individuals across multiple families (PMID: 1301940, 1352322; ClinVar SCV002506353.1). This variant has been identified in 5/282858 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	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	Hypercholesterolemia, familial, 1	2019-05-23	criteria provided, single submitter	research
Revvity Omics, Revvity	RCV000211583	SCV002017135	pathogenic	Hypercholesterolemia, familial, 1	2019-12-19	criteria provided, single submitter	clinical testing
AiLife Diagnostics, AiLife Diagnostics	RCV000162016	SCV002502848	likely pathogenic	not provided	2022-01-18	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002433637	SCV002753386	pathogenic	Cardiovascular phenotype	2022-08-30	criteria provided, single submitter	clinical testing	The p.E101K pathogenic mutation (also known as c.301G>A), located in coding exon 3 of the LDLR gene, results from a G to A substitution at nucleotide position 301. The glutamic acid at codon 101 is replaced by lysine, an amino acid with similar properties. This alteration has been detected in multiple individuals with familial hypercholesterolemia from various countries (Loux N et al. Hum. Mutat., 1992;1:325-32; Hobbs HH et al. Hum. Mutat., 1992;1:445-66; Webb JC et al. J. Lipid Res., 1992 May;33:689-98; Wang J et al. Hum. Mutat., 2001 Oct;18:359; Mozas P et al. Hum. Mutat., 2004 Aug;24:187; Robles-Osorio L et al. Arch. Med. Res., 2006 Jan;37:102-8; Miyake Y et al. Atherosclerosis, 2009 Mar;203:153-60; Al-Khateeb A et al. BMC Med. Genet., 2011 Mar;12:40). This alteration has also been reported to segregate with disease in families (Loux N et al. Hum. Mutat., 1992;1:325-32; Webb JC et al. J. Lipid Res., 1992 May;33:689-98). In addition, this alteration was shown to impact LDLR protein expression and activity (Hobbs HH et al. Hum. Mutat., 1992;1:445-66; Webb JC et al. J. Lipid Res., 1992 May;33:689-98). Furthermore, internal structural analysis indicates that this variant, which impacts a residue in the conserved cluster of acidic amino acids at the C-terminal end of LDLR class A repeat 2, is expected to have a deleterious impact on protein function (Jeon H and Blacklow C. Annu. Rev. Biochem. 2005;74:535-62; Ambry internal data). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Genetics and Molecular Pathology, SA Pathology	RCV000211583	SCV002761493	pathogenic	Hypercholesterolemia, familial, 1	2021-05-18	criteria provided, single submitter	clinical testing
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	RCV000775032	SCV004046143	pathogenic	Familial hypercholesterolemia		criteria provided, single submitter	clinical testing	This variant has been previously reported as a heterozygous change in patients with familial hypercholesterolemia (PMID: 9259195, 1301956, 1352322, 25248394). Different amino acid changes at the same residue (p.E101A, p.E101=, p.E101*, and p.E101V) have been previously reported in individuals with familial hypercholesterolemia (PMID: 33740630, 34297352, 7573037, 30400955). Functional studies showed that the c.301G>A (p.Glu101Lys) variant resulted in decreased receptor activity, alteration to protein processing, and intracellular transport (PMID: 1301956, 9026534, 25647241). The c.301G>A (p.Glu101Lys) variant is present in the heterozygous state in the gnomAD population database at a frequency of 0.002% (5/282858) and thus is presumed to be rare. The c.301G>A (p.Glu101Lys) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Based on the available evidence, the c.301G>A (p.Glu101Lys) variant is classified as Pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000162016	SCV004219980	pathogenic	not provided	2022-09-02	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.000031 (4/129168 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in affected individuals with familial hypercholesterolemia (PMIDs: 1301940 (1992), 7562961 (1995), 9676383 (1998), 15914792 (2005), 16314194 (2006), 17142622 (2006), 21310417 (2011), 21418584 (2011), 23669246 (2013), 32331935 (2020), 33740630 (2021), and 34037665 (2021). Functional studies found that this variant impacts protein function (PMIDs: 1352322 (1992) and 25647241 (2015)). 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	RCV000211583	SCV004820146	pathogenic	Hypercholesterolemia, familial, 1	2024-01-08	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with lysine at codon 101 in the LDLR type A repeat 2 of the ligand binding domain of the LDLR protein. This variant is also known as p.Glu80Lys in the mature protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Experimental studies have shown that this variant significantly inhibits LDL uptake (PMID: 25647241). This LDLR variant has been reported in over 20 heterozygous individuals affected with familial hypercholesterolemia (PMID: 1301940, 1352322, 11668627, 11668640, 15241806, 16314194, 17142622, 18718593, 19843101, 20236128, 23669246, 31345425, 32331935, 33740630, 34037665, 36499307; Color internal data). This variant has also been observed in compound heterozygous state with a known pathogenic LDLR variant in two individuals affected with severe homozygous familial hypercholesterolemia, a phenotype expected of having two deleterious LDLR variants (PMID: 1352322, 37119068). It has been shown that this variant segregates with disease in multiple affected individuals across multiple families (PMID: 1301940, 1352322; ClinVar SCV002506353.1). This variant has been identified in 5/282858 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.
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	RCV002051659	SCV000190284	likely pathogenic	Hypercholesterolemia	2014-06-01	no assertion criteria provided	research
Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital	RCV000211583	SCV000268550	pathogenic	Hypercholesterolemia, familial, 1	2008-06-05	no assertion criteria provided	clinical testing
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	RCV000211583	SCV000606069	pathogenic	Hypercholesterolemia, familial, 1		no assertion criteria provided	research