Submissions for variant NM_000527.5(LDLR):c.2441G>A (p.Arg814Gln)

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
LDLR-LOVD, British Heart Foundation	RCV000237126	SCV000296010	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	RCV000237126	SCV000503489	likely benign	Hypercholesterolemia, familial, 1	2016-12-16	criteria provided, single submitter	clinical testing	subjects mutated among 2600 FH index cases screened = 3 , family member = 1/previously described in association with FH/Software predictions: Conflicting
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille	RCV000237126	SCV000583953	likely pathogenic	Hypercholesterolemia, familial, 1	2024-01-31	criteria provided, single submitter	clinical testing	This missense variant LDLR c.2441G>A (also known as p.Arg793Gln in the mature protein), replaces an arginine with glutamine at codon 814 of the LDLR protein (p.Arg814Gln). 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 “Likely Pathogenic” from evidence as follows. It is located within a highly conserved functional domain (Cytoplasmic domain) essential for LDLR internalization. This variant was historically assessed in-vivo (PM3) and in-vitro in homozygous FH (PS3-moderate), observed as a founder mutation for FH (PS4) or a polymorphism at risk of hypercholesterolemia in populations of African ancestry, and was estimated as pathogenic in-silico (REVEL= 0,768) by disrupting a domain required for MYLIP-triggered down-regulation of LDLR (PP3). However, discrepant observations in mildly hypercholesterolemic or normolipidemic subjects, a high frequency in the general population (GnomAD= 0.00111, with no homozygotes) and lack of high-level in-vitro functional studies lead to classify this variant as “Likely Pathogenic” with low penetrance.
Laboratory of Genetics and Molecular Cardiology, University of São Paulo	RCV000237126	SCV000588667	uncertain significance	Hypercholesterolemia, familial, 1	2016-03-01	criteria provided, single submitter	research
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001420704	SCV000697230	likely benign	not specified	2023-03-07	criteria provided, single submitter	clinical testing	Variant summary: LDLR c.2441G>A (p.Arg814Gln) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00036 in 282994 control chromosomes, predominantly at a frequency of 0.0037 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 3.7 fold of the estimated maximal expected allele frequency for a pathogenic variant in LDLR causing Early Onset Coronary Artery Disease phenotype (0.001), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. c.2441G>A has been reported in the literature in individuals affected with hypercholesterolemia without strong evidence for causality (e.g. Arca_1997, Thiart_2000, Vergotine_2001, Humphries_2006, Sanchez-Hernandez_2016, Futema_2021, DErasmo_2021, Rimbert_2022). These reports do not provide unequivocal conclusions about association of the variant with Early Onset Coronary Artery Disease. One co-occurrence with another pathogenic variants has been reported (LDLR c.2389G>A, p.Val797Met), providing supporting evidence for a benign role. At least one publication reports a modest reduction of LDL-R activity in-vivo in a patient with the variant (e.g. Arca_1997). Twelve ClinVar submitters (evaluation after 2014) cite this variant as benign (n=2), likely benign (n=4), uncertain significance (n=5) and likely pathogenic (n=1). Multiple laboratories reported the variant with conflicting assessments. Based on the evidence outlined above, the variant was classified as likely benign.
Invitae	RCV000776249	SCV000752439	likely benign	Familial hypercholesterolemia	2024-01-27	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000776249	SCV000911501	likely benign	Familial hypercholesterolemia	2020-01-23	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000162024	SCV002046453	uncertain significance	not provided	2023-09-21	criteria provided, single submitter	clinical testing	In the published literature, this variant has been reported in several individuals affected with hypercholesterolemia (PMIDs: 10882754 (2000), 11845603 (2001), 16250003 (2005), 16389549 (2006), 24529145 (2014), 26802169 (2016), 28220743 (2017), 30293936 (2018), 34040191 (2021), 35047021 (2021), 36769678 (2023)). In addition, this variant was also reported to occur with other variants in affected individuals (PMIDs: 27784735 (2016), 34496902 (2021)). Functional studies of this variant reported reduced LDLR degradation (PMID: 9544746 (1998)) and that the variant did not disrupt LDL uptake activity (PMID: 25647241 (2015)), however, further research is needed. The frequency of this variant in the general population, 0.0037 (93/24970 chromosomes in African/African American subpopulation (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is higher than would generally be expected for pathogenic variants in this gene. 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, we are unable to determine the clinical significance of this variant.
Mendelics	RCV001420704	SCV002518186	benign	not specified	2023-08-22	criteria provided, single submitter	clinical testing
GeneDx	RCV000162024	SCV002568620	uncertain significance	not provided	2022-03-14	criteria provided, single submitter	clinical testing	Identified in individuals with confirmed or suspected familial hypercholesterolemia (FH) (Arca et al., 1998; Vergotine et al., 2001; Fouchier et al., 2005; Humphries et al., 2006; Lange et al., 2014; Santos et al., 2014; Sanchez-Hernandez et al., 2016; Martin-Campos et al., 2018; Futema et al., 2021), familial combined hyperlipidemia (Minicocci et al., 2015), coronary heart disease (Thiart et al., 2000), and/or a history of early myocardial infarction (Do et al., 2015); In silico analysis supports that this missense variant does not alter protein structure/function; Published functional studies demonstrate conflicting results with some studies showing significantly lower fractional catabolic rate which suggests reduced in vivo LDL receptor activity (Arca et al., 1998), while other studies show LDL uptake is similar to wild type suggesting no functional impact (Thormaehlen et al., 2015); Also known as R793Q; This variant is associated with the following publications: (PMID: 26332594, 35047021, 24055113, 25637381, 25487149, 10882754, 24507775, 16250003, 16389549, 24529145, 25647241, 32906206, 11845603, 26342331, 27784735, 30293936, 33508743, 9544746, 32719484)
Ambry Genetics	RCV002453471	SCV002737601	benign	Cardiovascular phenotype	2022-10-19	criteria provided, single submitter	clinical testing	This alteration is classified as benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
New York Genome Center	RCV000237126	SCV002764304	uncertain significance	Hypercholesterolemia, familial, 1	2021-07-02	criteria provided, single submitter	clinical testing	The c.2441G>A (p.Arg814Gln) variant identified in the LDLR gene substitutes a moderately conserved Arginine for Glutamine at amino acid 814/861(exon 17/18). This variant is found with appreciable frequency in gnomAD(v3.1.1), including in two homozygotes (168 heterozygotes, 2 homozygotes; allele frequency:1.11e-3), which is higher than expected for a pathogenic variant in the LDLR gene. The c.2441G>A (p.Arg814Gln) variant is reported in ClinVar as Pathogenic, Likely Pathogenic, Likely Benign, and as a Variant of Uncertain Significance (VarID:161278). This variant has been identified in many affected individuals in the literature, although its role in relation to hyperlipidemia in those individuals is not clearly defined [PMID:9544746, 10882754, 16389549, 27784735, 33508743]. In silico algorithms predict this variant to be Damaging (SIFT; score:0.00) and Pathogenic (REVEL; score:0.768) to the function of the canonical transcript. While the c.2441G>A(p.Arg814Gln) variant identified in the LDLR gene has been identified in many affected individuals in the literature and is predicted damaging by in silico predictors, its allele frequency is higher than expected. Given the conflicting evidence regarding its pathogenicity, the c.2441G>A (p.Arg814Gln) variant identified in the LDLR gene is reported as a Variant of Uncertain Significance.
CeGaT Center for Human Genetics Tuebingen	RCV000162024	SCV002822511	benign	not provided	2022-11-01	criteria provided, single submitter	clinical testing	LDLR: BS1, BS2
Dept. of Genetics and Pharmacogenomics, Merck Research Labs	RCV000162024	SCV000189627	not provided	not provided		no assertion provided	in vitro
CSER _CC_NCGL, University of Washington	RCV002051671	SCV000190298	uncertain significance	Hypercholesterolemia	2014-06-01	no assertion criteria provided	research
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	RCV000237126	SCV000606653	pathogenic	Hypercholesterolemia, familial, 1		no assertion criteria provided	research
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000162024	SCV001553978	uncertain significance	not provided		no assertion criteria provided	clinical testing	The LDLR p.Arg646Gln variant was identified in 4 of 1430 proband chromosomes (frequency: 0.0028) from individuals or families with familial hypercholesterolemia (FH) or high LDL-C (Humphries_2006_PMID:16389549; Thiart_2000_PMID:10882754; Santos_2014_PMID:24529145; Lange_2014_PMID:24507775). The variant was also identified in dbSNP (ID: rs5928), LOVD 3.0 and ClinVar (classified as likely benign by 4 submitters, as a VUS by 3 submitters, as likely pathogenic by 1 submitter and as pathogenic by 1 submitter). The variant was identified in control databases in 101 of 282836 chromosomes at a frequency of 0.000357 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 93 of 24970 chromosomes (freq: 0.003724), Other in 1 of 7224 chromosomes (freq: 0.000138), Latino in 4 of 35440 chromosomes (freq: 0.000113), South Asian in 1 of 30614 chromosomes (freq: 0.000033) and European (non-Finnish) in 2 of 129174 chromosomes (freq: 0.000015), while the variant was not observed in the Ashkenazi Jewish, East Asian or European (Finnish) populations. The p.Arg646 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.