Submissions for variant NM_000527.5(LDLR):c.2231G>A (p.Arg744Gln)

Total submissions: 24

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	RCV000172965	SCV002817147	likely benign	Hypercholesterolemia, familial, 1	2022-05-27	reviewed by expert panel	curation	The NM_000527.5(LDLR): c.2231G>A (p.Arg744Gln) variant is classified as Likely benign for Familial Hypercholesterolemia by applying evidence codes BP4, BP2 and PS3_supporting as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: BP4 - REVEL score is 0.291. It is below 0.5, so splicing evaluation is required. Functional data on splicing is not available. A) Variant not on limits. B) Variant is exonic and within range, but it does not create a de novo AG or GT site. The variant is not predicted to alter splicing. BP2 - 2 individuals from Ambry Genetics: Patient 1 has LDLR p.Gln33* in trans. Phenotype LDL 111 mg/dl (on treatment); Patient 2 has LDLR p.Gly373Asp in trans. Phenotype = "high chol". PS3_supporting - level 3 assay (PMID: 9409298) - Heterozygous patients' lymphoblasts, immunoblotting, I125-LDL assay: no precursor detectable, degradation of 125I-LDL = 73%. Variant has 2 Supporting evidence codes towards Benign, enough to classify as Likely benign, and only 1 Supporting evidence code towards Pathogenic. The Benign criteria overwhelms the Pathogenic criteria, so we are confident in classifying this variant as Likely benign.
Cardiovascular Biomarker Research Laboratory, Mayo Clinic	RCV000172965	SCV000266322	likely benign	Hypercholesterolemia, familial, 1	2016-08-31	criteria provided, single submitter	research	MAF =<0.3%.
LDLR-LOVD, British Heart Foundation	RCV000172965	SCV000295924	likely benign	Hypercholesterolemia, familial, 1	2016-03-25	criteria provided, single submitter	literature only
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000172965	SCV000296928	likely benign	Hypercholesterolemia, familial, 1	2015-07-30	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	RCV000172965	SCV000503475	benign	Hypercholesterolemia, familial, 1	2016-12-16	criteria provided, single submitter	clinical testing	subjects mutated among 2600 FH index cases screened = 7 / previously described in association with FH/Software predictions: Benign
Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation	RCV000172965	SCV000540903	likely benign	Hypercholesterolemia, familial, 1	2017-03-23	criteria provided, single submitter	clinical testing
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille	RCV000172965	SCV000583935	likely benign	Hypercholesterolemia, familial, 1	2017-03-30	criteria provided, single submitter	clinical testing
Laboratory of Genetics and Molecular Cardiology, University of São Paulo	RCV000172965	SCV000588644	uncertain significance	Hypercholesterolemia, familial, 1	2016-03-01	criteria provided, single submitter	research
Labcorp Genetics (formerly Invitae), Labcorp	RCV001082553	SCV000627030	likely benign	Familial hypercholesterolemia	2021-11-02	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000058922	SCV000697223	likely benign	not provided	2017-06-01	criteria provided, single submitter	clinical testing	Variant summary: The LDLR c.2231G>A (p.Arg744Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant is located outside of any known functional domain or repeat. 4/4 in silico tools predict benign outcome for this variant (SNP&GO was not used due to a low reliability index), however no experimental studies were published at the time of evaluation (ACMG BP4). The variant of interest has been identified in a large, broad control datasets of ExAC at a frequency of 0.0008 (99/121250 chrs tested), reaching the 0.0011 in several sub-populations (South Asians and European NF) including 1 homozygote. Although the observed frequency is similar to the estimated maximal expected allele frequency of a pathogenic LDLR variant (~0.001), thus supporting benign interpretation, the information on lipid profiling in these individuals is not available for individual review. The variant of interest was reported in multiple patients with elevated cholesterol level, including patient(s) carrying a known pathogenic variant APOB p.R3500Q (ACMG BP5), in whom lipid profiling results were not significantly different from data observed in patients carrying APOB R3500Q alone (Brusgaard, 2006) (ACMG BP5). In addition, per Dutch FH-database, cholesterol levels of R723Q positive and R723Q negative relatives are virtually similar (ACMG BS4), again favoring benign classification. The c.2231G>A was identified heterozygously in a healthy Caucasian adult undergoing carrier screening (ACMG BS2). Lastly, multiple clinical diagnostic laboratories/reputable databases classified this variant as Benign/Likely Benign (ACMG BP6). Considering all evidence the variant was conservatively classified as Likely Benign until additional evidence supporting its presence in normolipedimic control subjects is obtained.ACMG Classification: BRationale for Pathogenicity: none. Rationale for being Benign: BS2, BS4, BP4, BP5; BP6 was not engaged due to discordant classifications.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000058922	SCV000888165	benign	not provided	2022-12-23	criteria provided, single submitter	clinical testing
GeneDx	RCV000058922	SCV000977871	likely benign	not provided	2018-06-18	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.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV000058922	SCV000987540	likely benign	not provided		criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000058922	SCV001151673	likely benign	not provided	2024-09-01	criteria provided, single submitter	clinical testing	LDLR: BP4, BS1
Illumina Laboratory Services, Illumina	RCV000172965	SCV001286053	likely benign	Hypercholesterolemia, familial, 1	2017-04-27	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.
Institute of Human Genetics, University Hospital Muenster	RCV000172965	SCV002577918	likely benign	Hypercholesterolemia, familial, 1	2023-12-31	criteria provided, single submitter	clinical testing	ACMG categories: BP1,BP4
Ambry Genetics	RCV002426620	SCV002730922	benign	Cardiovascular phenotype	2016-04-13	criteria provided, single submitter	clinical testing	This alteration is classified as 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.
SNPedia	RCV000058922	SCV000090443	not provided	not provided		no assertion provided	not provided
Dept. of Genetics and Pharmacogenomics, Merck Research Labs	RCV000058922	SCV000189587	not provided	not provided		no assertion provided	in vitro
Institute for Integrative and Experimental Genomics, University of Luebeck	RCV000172965	SCV000212142	likely pathogenic	Hypercholesterolemia, familial, 1		flagged submission	research
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	RCV000172965	SCV000606616	benign	Hypercholesterolemia, familial, 1		no assertion criteria provided	research
Natera, Inc.	RCV001082553	SCV001461328	likely benign	Familial hypercholesterolemia	2020-09-16	no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV001698956	SCV001919757	benign	not specified		no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000058922	SCV001963279	likely benign	not provided		no assertion criteria provided	clinical testing