Submissions for variant NM_000527.5(LDLR):c.829G>A (p.Glu277Lys)

Total submissions: 25

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Cardiovascular Biomarker Research Laboratory, Mayo Clinic	RCV000210246	SCV000266310	likely benign	Hypercholesterolemia, familial, 1	2015-08-31	criteria provided, single submitter	research	MAF =<0.3%, likely pathogenic based on the integrative in-silico score. "Little/No effect" on the LDL receptor activity based on experimental validation.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000776470	SCV000285034	benign	Familial hypercholesterolemia	2024-01-31	criteria provided, single submitter	clinical testing
LDLR-LOVD, British Heart Foundation	RCV000210246	SCV000295006	likely benign	Hypercholesterolemia, familial, 1	2016-03-25	criteria provided, single submitter	literature only
Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge	RCV000210246	SCV000322918	uncertain significance	Hypercholesterolemia, familial, 1	2016-03-01	criteria provided, single submitter	research	0/190 non-FH alleles; 0/60 healthy control individuals
Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix	RCV000210246	SCV000503243	benign	Hypercholesterolemia, familial, 1	2016-12-16	criteria provided, single submitter	clinical testing	subjects mutated among 2600 FH index cases screened = 15 , family members = 5 / for 14 index cases among 15 this variant is associated with c.1268T>C, p.Ile423Thr that seems to be more deleterious / Software predictions: Conflicting
Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation	RCV000210246	SCV000540898	uncertain significance	Hypercholesterolemia, familial, 1	2017-03-20	criteria provided, single submitter	clinical testing
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille	RCV000210246	SCV000583745	likely benign	Hypercholesterolemia, familial, 1	2024-01-31	criteria provided, single submitter	clinical testing	This missense variant LDLR c.829G>A (also known as p.Glu256Lys in the mature protein), replaces a glutamic acid with lysine at codon 277 of the LDLR protein (p.Glu277Lys). 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 reclassified as “Likely Benign” from evidence as follows. It is located within a moderately conserved (REVEL=0.33) functional domain (LDLR Class A7) involved in LDL binding with LDL receptors (BP4). It is observed with a frequency exceeding 0.02% in the general population (GnomAD= 0.000375, no homozygotes) and despite apparent cosegregation in some families, it has been often reported in Cis with other proven pathogenic variants, and notably with the c.1268T>C (p.Ile423Thr) in populations of European ancestry (BP2). Finally, several independent level 1 in-vitro functional studies have shown consistently that this variant has a neutral effect on LDLR function (BS3).
Laboratory of Genetics and Molecular Cardiology, University of São Paulo	RCV000210246	SCV000588522	uncertain significance	Hypercholesterolemia, familial, 1	2016-03-01	criteria provided, single submitter	research
GeneDx	RCV000610848	SCV000730507	likely benign	not specified	2017-12-29	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Iberoamerican FH Network	RCV000210246	SCV000748041	uncertain significance	Hypercholesterolemia, familial, 1	2016-03-01	criteria provided, single submitter	research
Color Diagnostics, LLC DBA Color Health	RCV000776470	SCV000912020	benign	Familial hypercholesterolemia	2018-08-27	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000610848	SCV000917586	benign	not specified	2021-02-01	criteria provided, single submitter	clinical testing	Variant summary: LDLR c.829G>A (p.Glu277Lys) results in a conservative amino acid change located in a class A repeat (IPR002172) in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00054 in 251484 control chromosomes, predominantly within the South Asian and Southern European subpopulations at a frequency of 0.0016 and 0.0012, respectively (gnomAD). The observed variant frequency in these subpopulations is close to- or higher than the expected allele frequency for a pathogenic variant in LDLR causing Familial Hypercholesterolemia phenotype (0.0013), strongly suggesting that the variant is a benign polymorphism. c.829G>A has been reported in the literature in individuals affected with Familial Hypercholesterolemia, but also in controls (e.g. Ekstrom_1995, Pereira_1995, Descamps_1997, Ekstrom_2000, Weiss_2000, Fouchier_2001, Bertolini_2000, Mozas_2004. Ejarque_2008). Of note, in many of these patients co-occurrences with other pathogenic variants in cis have been reported (e.g. c.12G>A (p.Trp4X), c.460C>T (p.Gln154X), c.1326C>G (p.Tyr442X), c.2393_2401del9; see e.g. in Mozas_2004), providing supporting evidence for a benign role. Publications also reported experimental evidence evaluating an impact on protein function, and demonstrated normal expression level, and LDL uptake for the variant protein (e.g. Ekstrom_2000, Thormaehlen_2015, RodriguezJimenez_2019). 13 other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments. Based on the evidence outlined above, the variant was classified as benign.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000161968	SCV001134270	likely benign	not provided	2023-01-11	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000210246	SCV001285929	likely benign	Hypercholesterolemia, familial, 1	2018-03-12	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Laboratory of Molecular Genetics, National Medical Research Center for Therapy and Preventive Medicine	RCV000776470	SCV001482458	uncertain significance	Familial hypercholesterolemia		criteria provided, single submitter	research
Genome-Nilou Lab	RCV000210246	SCV001653437	uncertain significance	Hypercholesterolemia, familial, 1	2021-05-18	criteria provided, single submitter	clinical testing
Mendelics	RCV000610848	SCV002518179	uncertain significance	not specified	2022-05-04	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002426795	SCV002679277	likely benign	Cardiovascular phenotype	2018-05-30	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, 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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000161968	SCV004562166	likely benign	not provided	2023-04-24	criteria provided, single submitter	clinical testing
Dept. of Genetics and Pharmacogenomics, Merck Research Labs	RCV000161968	SCV000189543	not provided	not provided		no assertion provided	in vitro
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	RCV000210246	SCV000606243	benign	Hypercholesterolemia, familial, 1		no assertion criteria provided	research
Clinical Genetics, Academic Medical Center	RCV000610848	SCV001918264	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000161968	SCV001974936	likely benign	not provided		no assertion criteria provided	clinical testing
Natera, Inc.	RCV000776470	SCV002086390	likely benign	Familial hypercholesterolemia	2020-04-03	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003927530	SCV004746859	likely benign	LDLR-related disorder	2021-04-07	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).