Submissions for variant NM_000527.5(LDLR):c.1576C>T (p.Pro526Ser)

gnomAD frequency: 0.00001  dbSNP: rs730882106

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	RCV000238217	SCV001960928	uncertain significance	Hypercholesterolemia, familial, 1	2021-06-09	reviewed by expert panel	curation	NM_000527.5(LDLR):c.1576C>T (p.Pro526Ser) variant is classified as variant of Uncertain significance for Familial Hypercholesterolemia by applying evidence codes (PM2, PP3, PP4 and PS4_Supportive) 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: PM2 - PopMax MAF = 0.00002326 (0.002%) in European-non Finnish exomes (gnomAD v2.1.1). PP3 - REVEL: 0,952. PP4 - Variant meets PM2. Variant identified in 5 index cases (1 case from Color laboratory with Simon-Broome criteria; 1 case from GeneDx laboratory with Simon Broome criteria; 1 cases from University of British Columbia with DLCN criteria; 2 cases fulfilling Simeon-Broome criteria published in PMID: 9259195). PS4_supporting - Variant meets PM2. Variant identified in 5 index cases.
LDLR-LOVD, British Heart Foundation	RCV000238217	SCV000295505	likely pathogenic	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	RCV000238217	SCV000503367	likely pathogenic	Hypercholesterolemia, familial, 1	2016-12-16	criteria provided, single submitter	clinical testing	subjects mutated among 2600 FH index cases screened = 4 , family members = 3 / FH-Cincinnati-3, 5% to 15% LDLR Activity / Software predictions: Damaging
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000455448	SCV000539511	uncertain significance	not specified	2016-03-28	criteria provided, single submitter	clinical testing	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: 3 papers, 1 describing in vitro study suggesting functional impact, 1 report in a control. Reported in ExAC: 2/66098 European chromosomes
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille	RCV000238217	SCV000583850	pathogenic	Hypercholesterolemia, familial, 1	2017-03-30	criteria provided, single submitter	clinical testing
Invitae	RCV000775072	SCV000627019	pathogenic	Familial hypercholesterolemia	2024-01-27	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 526 of the LDLR protein (p.Pro526Ser). This variant is present in population databases (rs730882106, gnomAD 0.002%). This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 1301956, 9259195, 11462246, 27497240; Invitae). This variant is also known as p.Pro505Ser. ClinVar contains an entry for this variant (Variation ID: 183120). 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: 1301956, 25647241). For these reasons, this variant has been classified as Pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000775072	SCV000909174	likely pathogenic	Familial hypercholesterolemia	2023-10-18	criteria provided, single submitter	clinical testing	This missense variant replaces proline with serine at codon 526 in the third LDLR type B repeat of the EGF precursor homology domain of the LDLR protein. This variant is also known as p.Pro505Ser in the mature protein; FH Cincinnati-3. 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). A functional study has shown that this variant interferes with protein transport and significantly affects LDLR biosynthesis or turnover (PMID: 25647241). Another functional study has shown significantly reduced LDLR activity (5-15% of the wild type) in cells from an individual with heterozygous hypercholesterolemia (PMID: 1301956). This variant has been reported in over 10 individuals affected with familial hypercholesterolemia (PMID: 1301956, 9259195, 10208479, 11462246, 27497240, 31345425, 34037665; Color internal data). This variant has been identified in 3/282624 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000161994	SCV001134254	likely pathogenic	not provided	2022-11-11	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.000023 (3/128988 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in individuals with hypercholesterolemia (PMID: 9259195 (1997), 11462246 (2001), 27497240 (2016), 31345425 (2019), 34037665 (2021)). Functional studies have reported that this variant is damaging by causing LDLR activity to decrease to 5% to 15% of wildtype (PMID: 1301956 (1992)) that is likely due to an error in biosynthesis or turnover (PMID: 25647241 (2015)). 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, this variant is classified as likely pathogenic.
Brunham Lab, Centre for Heart and Lung Innovation, University of British Columbia	RCV000238217	SCV001432657	likely pathogenic	Hypercholesterolemia, familial, 1	2019-03-03	criteria provided, single submitter	research
GeneDx	RCV000161994	SCV001792713	uncertain significance	not provided	2023-03-22	criteria provided, single submitter	clinical testing	Reported in several individuals with FH, some of which harbored an additional FH-related variant (Hobbs et al., 1992; Day et al., 1997; Nauck et al., 2001; Thormaehlen et al., 2015; Maurer et al., 2016); Also known as p.P505S and FH-Cincinnati-3; Not observed at significant frequency in large population cohorts (gnomAD); 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: 25647241, 27497240, 1301956, 25487149, 9259195, 30586733, 31401775, 31447099, 11462246, 34037665, 31345425, 26582918, 35753512, 10357843, 10208479, 19837725)
AiLife Diagnostics, AiLife Diagnostics	RCV000161994	SCV002501974	likely pathogenic	not provided	2021-06-29	criteria provided, single submitter	clinical testing
National Institute of Allergy and Infectious Diseases - Centralized Sequencing Program, National Institutes of Health	RCV000775072	SCV002522192	likely pathogenic	Familial hypercholesterolemia	2021-08-06	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002399589	SCV002710067	pathogenic	Cardiovascular phenotype	2021-01-20	criteria provided, single submitter	clinical testing	The p.P526S pathogenic mutation (also known as c.1576C>T and p.P505S), located in coding exon 10 of the LDLR gene, results from a C to T substitution at nucleotide position 1576. The proline at codon 526 is replaced by serine, an amino acid with similar properties. This variant has been detected in individuals with familial hypercholesterolemia (FH) and reduced LDL uptake was described in patient fibroblasts as well as by in vitro assays (Hobbs HH et al. Hum. Mutat., 1992;1:445-66; Day IN et al. Hum. Mutat., 1997;10:116-27; Nauck MS et al. Hum. Mutat., 2001 Aug;18:165-6; Maurer F et al. Swiss Med Wkly, 2016 Aug;146:w14326; Thormaehlen AS et al. PLoS Genet., 2015 Feb;11:e1004855). In addition, variants affecting the same amino acid, p.P526T, p.P526H and p.P526R, have been reported in association with FH (Chmara M et al. J. Appl. Genet., 2010;51:95-106; Marduel M et al. Hum. Mutat., 2010 Nov;31:E1811-24; Gonzalez-Garay ML et al. Proc. Natl. Acad. Sci. U.S.A., 2013 Oct;110:16957-62). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Dept. of Genetics and Pharmacogenomics, Merck Research Labs	RCV000161994	SCV000189569	not provided	not provided		no assertion provided	in vitro
Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals	RCV000238217	SCV000680104	likely pathogenic	Hypercholesterolemia, familial, 1	2017-05-29	no assertion criteria provided	clinical testing