Submissions for variant NM_000527.5(LDLR):c.259T>G (p.Trp87Gly)

gnomAD frequency: 0.00001  dbSNP: rs121908025

Total submissions: 25

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	RCV000003870	SCV001960956	pathogenic	Hypercholesterolemia, familial, 1	2021-06-07	reviewed by expert panel	curation	The NM_000527.5(LDLR):c.259T>G (p.Trp87Gly) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying evidence codes (PS3, PS4, PP1_Moderate, PM2, PP3 and PP4) 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: PS3 - Level 1/2 assays: PMID 31578082: Hmz patients' lymphocytes, FACS assays and Heterologous cells (CHO), WB, FACS and CLSM assays - results - lymphocytes: normal cell surface LDLR, 40% LDL-LDLR binding, 35% uptake; CHO: normal (100%) LDLR expression, 20% LDL-LDLR binding, 35% uptake ---- binding and uptake are below 70% of wild-type, so PS3 is Met. PS4 - Variant meets PM2. Variant identified in at least 13 unrelated index cases with Dutch Lipid Clinic score equal or above 6 from different labs. PP1_moderate - variant segregates with FH phenotype in 5 informative meiosis in 2 families from different labs. PM2 - PopMax MAF = 0.00005418 (0.0054%) in european non-finnish exomes (gnomAD v2.1.1). PP3 - REVEL = 0.892. PP4 - Variant meets PM2. Identified in 13 unrelated index cases with Dutch Lipid Clinic score equal or above 6 from different labs.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000844748	SCV000271387	pathogenic	Homozygous familial hypercholesterolemia	2015-12-21	criteria provided, single submitter	clinical testing	The p.Trp87Gly variant in LDLR is a well-established pathogenic variant for fami lial hypercholesterolemia (Leitersdorf 1990, Jensen 1996, Vohl 1997, Tybjaerg-Ha nsen 2005, Futema 2013), and is a known founder mutation in the French Canadian population where it has been reported in >400 individuals with FH, including >15 homozygous individuals (Vohl 1997). It has also been identified in 7/126722Euro pean chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broad institute.org; dbSNP rs121908025); however, this frequency is low enough to be c onsistent with the frequency of FH in the general population. Additionally, in v itro functional studies provide some evidence that the p.Trp87Gly variant may im pact protein function (Leitersdorf 1990). In summary, this variant meets our cri teria to be classified as pathogenic for FH in an autosomal dominant manner base d upon its identification in a large number of affected individuals and low freq uency in controls. ACMG/AMP Criteria applied: PS4; PM3; PM2_Supporting; PP3; PS3 _Supporting.
Invitae	RCV000776466	SCV000285027	pathogenic	Familial hypercholesterolemia	2024-01-02	criteria provided, single submitter	clinical testing	This sequence change replaces tryptophan, which is neutral and slightly polar, with glycine, which is neutral and non-polar, at codon 87 of the LDLR protein (p.Trp87Gly). This variant is present in population databases (rs121908025, gnomAD 0.006%). This missense change has been observed in individual(s) with familial hypercholesterolemia (PMID: 2318961, 12553167, 16542394). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It is commonly reported in individuals of European ancestry (PMID: 2318961, 12553167, 16542394). This variant is also known as p.W66G. ClinVar contains an entry for this variant (Variation ID: 3685). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt LDLR protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects LDLR function (PMID: 8098448). For these reasons, this variant has been classified as Pathogenic.
LDLR-LOVD, British Heart Foundation	RCV000003870	SCV000294560	likely pathogenic	Hypercholesterolemia, familial, 1	2016-03-25	criteria provided, single submitter	literature only
Robarts Research Institute, Western University	RCV000003870	SCV000484716	likely pathogenic	Hypercholesterolemia, familial, 1		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	RCV000003870	SCV000503120	likely pathogenic	Hypercholesterolemia, familial, 1	2016-12-16	criteria provided, single submitter	clinical testing	subjects mutated among 2600 FH index cases screened = 9 , family members = 7 with co-segregation / frequently associated with c.1975A>C, p.Thr659Pro (2 index cases), Subnormal LDLR activity / Software predictions: Damaging
Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation	RCV000003870	SCV000540721	likely pathogenic	Hypercholesterolemia, familial, 1	2016-11-05	criteria provided, single submitter	clinical testing
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille	RCV000003870	SCV000583644	pathogenic	Hypercholesterolemia, familial, 1	2017-03-30	criteria provided, single submitter	clinical testing
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV000622852	SCV000740415	likely pathogenic	not provided	2017-07-11	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000776466	SCV000912015	pathogenic	Familial hypercholesterolemia	2023-04-24	criteria provided, single submitter	clinical testing	This missense variant (also known as p.Trp66Gly in the mature protein) is located in the second LDLR type A repeat of the ligand binding domain of the LDLR protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Experimental functional studies have demonstrated that the variant protein showed reduced LDL binding (PMID: 8645371, 10735631, 31578082). This variant has been identified in over 500 individuals affected with familial hypercholesterolemia (PMID: 2318961, 8098448, 9104431, 9259195, 9272705, 9676383, 12553167, 15528480, 16542394, 23669246, 30512145, 31345425, 31578082, 33955087, 34037665). This variant is common in individuals of European descent and is considered a founder mutation in the French-Canadian population (PMID: 9272705) and Swedish population (PMID: 33955087). Homozygous individuals have shown much higher LDL-C levels than heterozygous individuals (PMID: 8098448, 36727130). This variant has been identified in 8/282882 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on available evidence, this variant is classified as Pathogenic.
Institute of Human Genetics, University of Leipzig Medical Center	RCV000003870	SCV001428736	pathogenic	Hypercholesterolemia, familial, 1	2023-12-06	criteria provided, single submitter	clinical testing	Criteria applied: PS3,PS4,PP1_MOD,PM2_SUP,PP3,PP4
Brunham Lab, Centre for Heart and Lung Innovation, University of British Columbia	RCV000003870	SCV001432641	pathogenic	Hypercholesterolemia, familial, 1	2019-03-13	criteria provided, single submitter	research
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	RCV000776466	SCV001435004	pathogenic	Familial hypercholesterolemia	2020-02-04	criteria provided, single submitter	clinical testing	The c.259T>G (p.Trp87Gly) variant in the LDLR gene has been reported in multiple individuals with familial hypercholesterolemia (PMID: 2318961, 8054972, 8645371, 9259195, 9104431). It is located in the functionally important second LDLR type A repeat. Functional studies have demonstrated a deleterious effect of the p.Trp87Gly variant on LDL binding (PMID: 2318961, 8645371, 10735631). The variant is observed in gnomAD at a low minor allele frequency (8/282882). Multiple algorithms predicted this change to be deleterious. Therefore, the c.259T>G (p.Trp87Gly) variant in the LDLR gene is classified as pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000776466	SCV001467951	pathogenic	Familial hypercholesterolemia	2020-12-14	criteria provided, single submitter	clinical testing	Variant summary: LDLR c.259T>G (p.Trp87Gly) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.8e-05 in 251490 control chromosomes. c.259T>G has been reported in the literature in multiple individuals affected with Familial Hypercholesterolemia (e.g. Leitersdorf_1990, Moorjani_1993, Banerjee_2019). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, indicating the cells expressing the variant have reduced LDL-binding and uptake (e.g. Banerjee_2019). 11 clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories cited the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Johns Hopkins Genomics, Johns Hopkins University	RCV000003870	SCV001711949	pathogenic	Hypercholesterolemia, familial, 1	2021-05-28	criteria provided, single submitter	clinical testing	This variant (rs121908025) is rare (<0.1%) in a large population database (gnomAD: 8/282882 total alleles, 0.003%, no homozygotes) and has an entry in ClinVar. It has been reported in multiple individuals with familial hypercholesterolemia-1, and is considered a founder mutation in the French-Canadian population. This variant is located in the second type A repeat of the ligand binding domain of the LDLR protein. Functional studies have demonstrated a deleterious effect of p.Trp87Gly on LDL binding and uptake. This variant was also identified in the patient's father, who has a personal history of elevated cholesterol. We consider c.259T>G to be pathogenic.
Mayo Clinic Laboratories, Mayo Clinic	RCV000622852	SCV001715234	pathogenic	not provided	2023-03-07	criteria provided, single submitter	clinical testing	PP3, PP4, PM2_supporting, PM3, PS3_supporting, PS4
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	RCV000003870	SCV001754778	pathogenic	Hypercholesterolemia, familial, 1	2020-02-04	criteria provided, single submitter	clinical testing	The c.259T>G (p.Trp87Gly) variant in the LDLR gene has been reported in multiple individuals with familial hypercholesterolemia (PMID: 2318961, 8054972, 8645371, 9259195, 9104431). It is located in the functionally important second LDLR type A repeat. Functional studies have demonstrated a deleterious effect of the p.Trp87Gly variant on LDL binding (PMID: 2318961, 8645371, 10735631). The variant is observed in gnomAD at a low minor allele frequency (8/282882). Multiple algorithms predicted this change to be deleterious. Therefore, the c.259T>G (p.Trp87Gly) variant in the LDLR gene is classified as pathogenic.
GeneDx	RCV000622852	SCV001818531	pathogenic	not provided	2022-08-19	criteria provided, single submitter	clinical testing	LDL receptor activity was significantly reduced in the fibroblasts from two of three unrelated individuals who were homozygous for the FH French Canadian-4 allele (Hobbs et al., 1992) and this variant affects either LDLR turnover or the binding of the LDLR protein to LDL (Leitersdorf et al., 1990); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 28008010, 9104431, 2318961, 9259195, 8645371, 15528480, 23669246, 24281370, 9767373, 12381843, 30586733, 30512145, 29874871, 29261184, 31401775, 29407885, 31727422, 34040191, 32041611, 33303402, 32719484, 32770674, 33740630, 34037665, 33087929, 9272705, 1301956, 16542394)
Revvity Omics, Revvity	RCV000003870	SCV002017127	pathogenic	Hypercholesterolemia, familial, 1	2023-12-14	criteria provided, single submitter	clinical testing
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV000003870	SCV002061569	likely pathogenic	Hypercholesterolemia, familial, 1	2021-05-20	criteria provided, single submitter	clinical testing	PS4, PM2_Supporting, PP3, PM1, PS3_Moderate
Ambry Genetics	RCV002426484	SCV002743312	pathogenic	Cardiovascular phenotype	2022-04-26	criteria provided, single submitter	clinical testing	The p.W87G pathogenic mutation (also known as c.259T>G), located in coding exon 3 of the LDLR gene, results from a T to G substitution at nucleotide position 259. The tryptophan at codon 87 is replaced by glycine, an amino acid with highly dissimilar properties. This mutation, historically reported as W66G, has been identified in multiple individuals with familial hypercholesterolemia (FH) (Leitersdorf E et al. J. Clin. Invest., 1990 Apr;85:1014-23; Brusgaard K et al. Clin. Genet., 2006 Mar;69:277-83; Langsted A et al. Lancet Diabetes Endocrinol, 2016 Jul;4:577-87). This alteration has been reported in FH patients across ethnic groups and has been designated a founder mutation in the French Canadian and Danish populations (Vohl MC et al. Clin. Genet., 1997 Jul;52:1-6; Jensen HK et al. Atherosclerosis, 1999 Oct;146:337-44). In vitro functional studies have demonstrated that this mutation causes defects in cell surface binding of LDL (Leitersdorf E et al. J. Clin. Invest., 1990 Apr;85:1014-23; Raungaard B et al. Clin. Genet., 2000 Feb;57:110-5). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
CeGaT Center for Human Genetics Tuebingen	RCV000622852	SCV002822505	pathogenic	not provided	2022-11-01	criteria provided, single submitter	clinical testing	LDLR: PM1, PM2, PP1:Moderate, PS4:Moderate, PP4, PS3:Supporting
OMIM	RCV000003870	SCV000024035	pathogenic	Hypercholesterolemia, familial, 1	1994-04-01	no assertion criteria provided	literature only
Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital	RCV000003870	SCV000268547	pathogenic	Hypercholesterolemia, familial, 1	2008-12-18	no assertion criteria provided	clinical testing
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	RCV000003870	SCV000606051	pathogenic	Hypercholesterolemia, familial, 1		no assertion criteria provided	research