Submissions for variant NM_000527.5(LDLR):c.1510A>G (p.Lys504Glu)

gnomAD frequency: 0.00002  dbSNP: rs730882103

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
LDLR-LOVD, British Heart Foundation	RCV000237290	SCV000295475	likely benign	Hypercholesterolemia, familial, 1	2016-03-25	criteria provided, single submitter	literature only
Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix	RCV000237290	SCV000503360	uncertain significance	Hypercholesterolemia, familial, 1	2016-12-16	criteria provided, single submitter	clinical testing	subject mutated among 2600 FH index cases screened = 1/Software predictions: Benign
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille	RCV000237290	SCV000583841	uncertain significance	Hypercholesterolemia, familial, 1	2024-01-31	criteria provided, single submitter	clinical testing	This missense variant LDLR: c.1510A>G (p.Lys504Glu), replaces lysine with glutamic acid at codon 504 of the LDLR protein. According to updated genomic data and to ClinGen FH VCEP criteria issued in 2022 (PMID: 34906454) for the validation of pathogenicity of LDLR variants, this variant may now be classified as “Variant of Uncertain Significance” from conflicting evidence as follows. This variant is located within a conserved (REVEL=0.529) functional domain (LDLR Class B3) involved in LDL receptor recycling to the plasma membrane (PP3-supporting). This variant is observed with a frequency <0.02% (PM2), in the general population (GnomAD= 0.0000197, no homozygotes). It was observed in hypercholesterolemic individuals and reported to cosegregate with FH in independent families of European ancestry (PS4-supporting). However, level 1 in-vitro functional studies have shown that this variant has a neutral effect on LDLR function (BS3).
Fundacion Hipercolesterolemia Familiar	RCV000237290	SCV000607606	uncertain significance	Hypercholesterolemia, familial, 1	2016-03-01	criteria provided, single submitter	research
Color Diagnostics, LLC DBA Color Health	RCV001175675	SCV001339364	uncertain significance	Familial hypercholesterolemia	2023-01-03	criteria provided, single submitter	clinical testing	This missense variant (also known as p.Lys483Glu in the mature protein) replaces lysine with glutamic acid at codon 504 of the LDLR protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). A cell-based experimental study has shown that this variant does not disrupt LDL uptake function of the protein (PMID: 25647241). This variant has been reported in individuals affected with familial hypercholesterolemia (PMID: 15199436, 25647241; Color internal data). This variant has also been observed in compound heterozygous state in individuals affected with homozygous familial hypercholesterolemia (PMID: 27784735). Additionally, this variant has been reported in individuals affected with myocardial infarction (PMID: 25487149). This variant has been identified in 3/251454 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV001175675	SCV001422594	uncertain significance	Familial hypercholesterolemia	2020-01-22	criteria provided, single submitter	curation	The p.Lys504Glu variant in LDLR has been reported in 1 Italian and 2 Norwegian individuals with familial hypercholesterolemia (PMID: 25647241, PMID: 15199436), but has been identified in 0.003% (3/113736) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs730882103). This variant has also been reported in ClinVar as having conflicint interpretations of pathogenicity (Variation ID: rs730882103). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PS4_supporting (Richards 2015).
Labcorp Genetics (formerly Invitae), Labcorp	RCV001175675	SCV003265100	benign	Familial hypercholesterolemia	2024-11-05	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000237290	SCV004822467	uncertain significance	Hypercholesterolemia, familial, 1	2024-06-09	criteria provided, single submitter	clinical testing	This missense variant (also known as p.Lys483Glu in the mature protein) replaces lysine with glutamic acid at codon 504 of the LDLR protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). A cell-based experimental study has shown that this variant does not disrupt LDL uptake function of the protein (PMID: 25647241). This variant has been reported in individuals affected with familial hypercholesterolemia (PMID: 15199436, 25647241; Color internal data). This variant has also been observed in compound heterozygous state in individuals affected with homozygous familial hypercholesterolemia (PMID: 27784735). Additionally, this variant has been reported in individuals affected with myocardial infarction (PMID: 25487149). This variant has been identified in 3/251454 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004526622	SCV005040352	uncertain significance	not specified	2024-03-13	criteria provided, single submitter	clinical testing	Variant summary: LDLR c.1510A>G (p.Lys504Glu) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251454 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1510A>G has been reported in the literature in individuals affected with Familial Hypercholesterolemia without strong evidence of causality (e.g. Alonso_2009, Sanchez-Hernandez_2016, Di Taranto_2021, Futema_2021). These reports do not provide unequivocal conclusions about association of the variant with Familial Hypercholesterolemia. At least one publication reports experimental evidence evaluating an impact on protein function (Thormaehlen_2015). These results showed no damaging effect of this variant. The following publications have been ascertained in the context of this evaluation (PMID: 19318025, 25647241, 27784735, 34297352, 33508743). ClinVar contains an entry for this variant (Variation ID: 183117). Based on the evidence outlined above, the variant was classified as uncertain significance.
Ambry Genetics	RCV004629153	SCV005135989	uncertain significance	Cardiovascular phenotype	2024-06-13	criteria provided, single submitter	clinical testing	The p.K504E variant (also known as c.1510A>G), located in coding exon 10 of the LDLR gene, results from an A to G substitution at nucleotide position 1510. The lysine at codon 504 is replaced by glutamic acid, an amino acid with similar properties. This alteration has been reported in familial hypercholesterolemia (FH) cohorts (Leren TP et al. Semin Vasc Med, 2004 Feb;4:75-85; Alonso R et al. Clin Biochem, 2009 Jun;42:899-903; S&aacute;nchez-Hern&aacute;ndez RM et al. Circ Cardiovasc Genet, 2016 Dec;9:504-510). This amino acid position is poorly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000161990	SCV005625818	uncertain significance	not provided	2024-07-29	criteria provided, single submitter	clinical testing	The LDLR c.1510A>G (p.Lys504Glu) variant has been reported in the published literature in individuals with familial hypercholesterolemia (PMIDs: 15199436 (2004), 19318025 (2009), 27784735 (2016), and 33508743 (2021)) as well as in individuals with early onset myocardial infarction (PMIDs: 25487149 (2015) and 25647241 (2015)). The ClinGen FH VCEP reported that this variant may now be classified as a Variant of Uncertain Significance (VUS) (PMID: 34906454 (2022)). The frequency of this variant in the general population, 0.000026 (3/113736 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is deleterious or benign. Based on the available information, we are unable to determine the clinical significance of this variant.
Dept. of Genetics and Pharmacogenomics, Merck Research Labs	RCV000161990	SCV000189565	not provided	not provided		no assertion provided	in vitro
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	RCV000237290	SCV000606446	benign	Hypercholesterolemia, familial, 1		no assertion criteria provided	research