Submissions for variant NM_000527.5(LDLR):c.806G>A (p.Gly269Asp)

Total submissions: 20

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	RCV000210247	SCV001960914	likely benign	Hypercholesterolemia, familial, 1	2021-06-07	reviewed by expert panel	curation	The NM_000527.5(LDLR):c.806G>A (p.Gly269Asp) variant is classified as Likely benign for Familial Hypercholesterolemia by applying evidence codes (BS2, BP2 and PP1_Moderate) 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: BS2 - Identified in 7 heterozygous controls from ABraOM database, and 2 non-affected family members from Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge. BP2 - variant identified in 2 Index cases with heterozygous FH phenotype and a 2nd LDLR variant classified as Pathogenic by these guidelines. PP1_moderate - variant segregates with phenotype in 5 informative meiosis in 3 families from Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge. Variant has 1 Strong and 1 Supporting evidence codes towards Benign, enough to classify as Likely benign, and only 1 Moderate 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	RCV000210247	SCV000266316	likely benign	Hypercholesterolemia, familial, 1	2015-08-31	criteria provided, single submitter	research	MAF =<0.3%. "Little/No effect" on the LDL receptor activity based on experimental validation.
LDLR-LOVD, British Heart Foundation	RCV000210247	SCV000294983	likely benign	Hypercholesterolemia, familial, 1	2016-03-25	criteria provided, single submitter	literature only
Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge	RCV000210247	SCV000322915	likely benign	Hypercholesterolemia, familial, 1	2016-03-01	criteria provided, single submitter	research	0/212 non-FH alleles
Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix	RCV000210247	SCV000503239	likely benign	Hypercholesterolemia, familial, 1	2016-12-16	criteria provided, single submitter	clinical testing	subjects mutated among 2600 FH index cases screened = 3 / FH-Rome-3 / Software predictions: Conflicting
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille	RCV000210247	SCV000583743	likely pathogenic	Hypercholesterolemia, familial, 1	2017-03-30	criteria provided, single submitter	clinical testing
Laboratory of Genetics and Molecular Cardiology, University of São Paulo	RCV000210247	SCV000588518	likely benign	Hypercholesterolemia, familial, 1	2016-03-01	criteria provided, single submitter	research
Fundacion Hipercolesterolemia Familiar	RCV000210247	SCV000607503	likely benign	Hypercholesterolemia, familial, 1	2016-03-01	criteria provided, single submitter	research
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000161966	SCV000697252	benign	not provided	2016-03-11	criteria provided, single submitter	clinical testing	Variant summary: c.806G>A affects a non-conserved nucleotide, resulting in amino acid change from Gly to Asp. 2/4 in-silico tools predict this variant to be benign (SNPs&GO not captured due to low reliability index). Functional study showed that the LDL uptake, binding capacity of LDL, and LDLR expression of variant were similar to those observed in control cells (Etxebarria_2012), indicating the neutral effect. This variant was found in 24/131566 control chromosomes at a frequency of 0.0001824. This variant has been reported in multiple FH patients without strong evidence for causality. Among the reported patients, variant was reported to co-occur with a deleterious LDLR variant c.1045delC in cis (Mozas_2004) and there is at least one family reported with lack of co-segregation of this variant with disease (Bourbon_2008). In addition, variant has been detected in early-onset myocardial infarction case with comparable allele frequency as in controls and multiple publications listed variant as nonpathogenic/benign (Do_2015, Etxebarre_2012, and Benito-Vicente_2015). Considering all, this variant is classified as Benign.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000775049	SCV000752451	likely benign	Familial hypercholesterolemia	2024-01-31	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000775049	SCV000909148	likely benign	Familial hypercholesterolemia	2018-07-10	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000210247	SCV001282942	uncertain significance	Hypercholesterolemia, familial, 1	2018-03-08	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. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Mendelics	RCV002247541	SCV002518178	benign	not specified	2023-08-22	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002415633	SCV002677567	likely benign	Cardiovascular phenotype	2019-05-28	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.
GeneDx	RCV000161966	SCV005080097	uncertain significance	not provided	2024-02-16	criteria provided, single submitter	clinical testing	Identified in patients with hypercholesterolemia and acute MI in published literature (PMID: 17765246, 25606447, 25741862, 36555767, 33740630, 35339733, 26332594, 15241806, 25487149, 23375686); however this variant was also observed in individuals with normal cholesterol levels and the variant did not segregate with disease in at least one family reported; Published functional studies suggest the p.(G269D) results in LDLR activity and expression and LDL uptake similar to wildtype (PMID: 21990180, 25647241); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as p.(G248D) and FH Rome-3; This variant is associated with the following publications: (PMID: 21990180, 15241806, 25647241, 26332594, 23375686, 25637381, 25487149, 32719484, 33740630, 36555767, 25741862, 25606447, 35339733, 17765246, 28145427)
Dept. of Genetics and Pharmacogenomics, Merck Research Labs	RCV000161966	SCV000189541	not provided	not provided		no assertion provided	in vitro
CSER _CC_NCGL, University of Washington	RCV002051672	SCV000190300	uncertain significance	Hypercholesterolemia	2014-06-01	no assertion criteria provided	research
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	RCV000210247	SCV000606229	pathogenic	Hypercholesterolemia, familial, 1		no assertion criteria provided	research
Iberoamerican FH Network	RCV000210247	SCV000748174	likely benign	Hypercholesterolemia, familial, 1	2016-03-01	no assertion criteria provided	research
Natera, Inc.	RCV000775049	SCV001453894	likely benign	Familial hypercholesterolemia	2020-01-01	no assertion criteria provided	clinical testing