Submissions for variant NM_000527.5(LDLR):c.2475C>G (p.Asn825Lys)

dbSNP: rs374045590

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	RCV000237920	SCV004022384	likely pathogenic	Hypercholesterolemia, familial, 1	2023-03-20	reviewed by expert panel	curation	The NM_000527.5 (LDLR):c.2475C>G (p.Asn825Lys) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying evidence codes (PM2, PP3, PS1, PP4, PS4_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: PM2: PopMax MAF = 0.00002 in European (Non-Finnish) in gnomAD (gnomAD v2.1.1). PP3: REVEL = 0.803. PS1: One other missense variant that leads to the same amino acid change at same codon, NM_000527.5 (LDLR):c.2475C>A (p.Asn825Lys), (ClinVarID 252341), is classified as Pathogenic by these guidelines. PP4: Variant meets PM2 and is identified in >1 index cases who fulfil FH diagnostic criteria after alternative causes of high cholesterol were excluded. PS4_Supporting: Variant meets PM2 and is identified in 5 index cases who fulfil FH diagnostic criteria. Four index cases met DLCN criteria for definite or probable FH: 1 case from Department of Medicine and Cardiology, Aarhus Amtssygehus University Hospital, Denmark, PMID 10532689; 1 case from Department of Vascular Medicine, Academic Medical Center at the University of Amsterdam, The Netherlands, PMID 11810272; 1 case from Robarts Research Institute, Canada, PMID 11668627; 1 case submitted to ClinVar from U4M - Lille University & CHRU Lille, France. One proband with LDLC >10mmol/l and xanthoma, reported by Jiang et al, 2016, Department of atherosclerosis, Capital Medical University, China, PMID 27830735.
LDLR-LOVD, British Heart Foundation	RCV000237920	SCV000296017	likely pathogenic	Hypercholesterolemia, familial, 1	2016-03-25	criteria provided, single submitter	literature only
Robarts Research Institute, Western University	RCV000237920	SCV000484701	likely pathogenic	Hypercholesterolemia, familial, 1		criteria provided, single submitter	clinical testing
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille	RCV000237920	SCV000583956	pathogenic	Hypercholesterolemia, familial, 1	2017-03-30	criteria provided, single submitter	clinical testing
Invitae	RCV001228564	SCV001400967	pathogenic	Familial hypercholesterolemia	2023-07-19	criteria provided, single submitter	clinical testing	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. ClinVar contains an entry for this variant (Variation ID: 161265). This variant is also known as N804K. This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 11668627, 18096825, 27765764, 27830735). This variant is present in population databases (rs374045590, gnomAD 0.0009%). This sequence change replaces asparagine, which is neutral and polar, with lysine, which is basic and polar, at codon 825 of the LDLR protein (p.Asn825Lys). Experimental studies have shown that this missense change affects LDLR function (PMID: 25378237). For these reasons, this variant has been classified as Pathogenic.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000237920	SCV001422630	pathogenic	Hypercholesterolemia, familial, 1	2020-01-22	criteria provided, single submitter	curation	The p.Asn825Lys variant in LDLR has been reported in 75 individuals (including 71 Norweigans, 2 Italian, and 1 Danish, and 1 Dutch individuals) with Familial Hypercholesterolemia, segregated with disease in 71 affected relatives from 19 families (PMID: 15199436, 11810272, 23375686, 11668627, 10532689), and has been identified in 0.001758% (2/113744) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs374045590). Please note that for diseases with clinical variability, or reduced penetrance, pathogenic variants may be present at a low frequency in the general population. This variant has also been reported likely pathogenic and pathogenic in ClinVar (Variation ID: 161265). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. One additional variant with the same amino acid change, c.2475C>A (p.Asn825Lys), has been reported pathogenic and likely pathogenic in association with disease in ClinVar and the literature, supporting that this variant is pathogenic (Variation ID: 252341). In summary, this variant meets criteria to be classified as pathogenic for Familial Hypercholesterolemia in an autosomal dominant manner based on multiple reports of individuals with disease and cosegregation with Familial Hypercholesterolemia. ACMG/AMP Criteria applied: PS4, PP1_Strong, PS1, PP3 (Richards 2015).
Revvity Omics, Revvity	RCV000237920	SCV002022673	likely pathogenic	Hypercholesterolemia, familial, 1	2020-02-15	criteria provided, single submitter	clinical testing
GeneDx	RCV002305450	SCV002599994	pathogenic	not provided	2023-09-29	criteria provided, single submitter	clinical testing	Reported in a patient with atrioventricular block in published literature (Resdal Dyssekilde et al., 2022); 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; Also known as p.(N804K); This variant is associated with the following publications: (PMID: 25637381, 25487149, 11137106, 11810272, 11668627, 15199436, 23375686, 28323660, 16424354, 17426749, 34407635, 34037665, 19318025, 21310417, 35470684, 10532689, 33740630, 18096825, 27830735, 15576851, 30777337, 37719435, 25378237)
Ambry Genetics	RCV002444605	SCV002735625	pathogenic	Cardiovascular phenotype	2023-04-14	criteria provided, single submitter	clinical testing	The p.N825K pathogenic mutation (also known as c.2475C>G), located in coding exon 17 of the LDLR gene, results from a C to G substitution at nucleotide position 2475. The asparagine at codon 825 is replaced by lysine, an amino acid with similar properties, and is located in the FxNPxY domain. This alteration (also referred to as N804K), and another nucleotide substitution (c.2475C>A) resulting in the same amino acid change have been detected in many individuals from familial hypercholesterolemia cohorts (Jensen HK et al. Atherosclerosis, 1999 Oct;146:337-44; Leren TP et al. Semin Vasc Med, 2004 Feb;4:75-85; Bertolini S et al. Atherosclerosis, 2013 Apr;227:342-8; Chaves FJ et al. J. Clin. Endocrinol. Metab., 2001 Oct;86:4926-32; Brusgaard K et al. Clin. Genet., 2006 Mar;69:277-83; Mozas P et al. Hum. Mutat., 2004 Aug;24:187). This alteration was also reported to segregate with hypercholesterolemia in several individuals in one family (Berge KE et al. Arterioscler. Thromb. Vasc. Biol., 2006 May;26:1094-100). In addition, experimental studies have indicated this alteration results in impaired LDL internalization and uptake (Etxebarria A et al. Hum. Mutat., 2015 Jan;36:129-41; Rodríguez-Jiménez C et al. Atherosclerosis, 2019 Jan). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
CSER _CC_NCGL, University of Washington	RCV002051658	SCV000190283	likely pathogenic	Hypercholesterolemia	2014-06-01	no assertion criteria provided	research
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	RCV000237920	SCV000606657	pathogenic	Hypercholesterolemia, familial, 1		no assertion criteria provided	research