Submissions for variant NM_000527.5(LDLR):c.1444G>A (p.Asp482Asn)

gnomAD frequency: 0.00004  dbSNP: rs139624145

Total submissions: 31

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	RCV000172963	SCV005328528	pathogenic	Hypercholesterolemia, familial, 1	2023-06-23	reviewed by expert panel	curation	The NM_000527.5(LDLR):c.1444G>A (p.Asp482Asn) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PS4, PP1_Strong, PM2, PP3 and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 23 June 2023. The supporting evidence is as follows: PM2: PopMax MAF = 0.00009 (0.009%) in European (Non-Finnish) exomes+genomes (gnomAD v2.1.1). PP3: REVEL=0.945. PS4, PP4: Variant meets PM2 and is identified in at least 14 unrelated index cases who fulfill criteria for FH (3 cases with Simon-Broome criteria from Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation, Czech Republic; 3 cases with DLCN score >=6 and 1 case with Simon-Broome criteria from Service de Biochimie et de Biologie Moléculaire, Hospices Civils de Lyon, Lyon, France; 3 cases with DLCN score >=6 from Robarts Research Institute, Canada; 3 cases with DLCN score >=6 from Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA, Australia; 1 case with DLCN score>=6 from Color Health, Inc, USA). PP1_Strong: Variant segregates with FH phenotype in at least 11 informative meioses in 4 families from different labs (Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation, Czech Republic and Service de Biochimie et de Biologie Moléculaire, Hospices Civils de Lyon, Lyon, France): 8 affected family members have the variant and 3 unaffected family members do not have the variant.
Institute for Integrative and Experimental Genomics, University of Luebeck	RCV000172963	SCV000212139	likely pathogenic	Hypercholesterolemia, familial, 1		criteria provided, single submitter	research
LDLR-LOVD, British Heart Foundation	RCV000172963	SCV000295433	likely pathogenic	Hypercholesterolemia, familial, 1	2016-03-25	criteria provided, single submitter	literature only
Robarts Research Institute, Western University	RCV000172963	SCV000484754	likely pathogenic	Hypercholesterolemia, familial, 1		criteria provided, single submitter	clinical testing
GeneDx	RCV000414235	SCV000491201	pathogenic	not provided	2024-01-12	criteria provided, single submitter	clinical testing	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; Functional studies showed that p.(D482N), when present in the homozygous or compound heterozygous state, results in decreased LDL receptor activity (PMID: 9026534); Also known as p.(D461N); This variant is associated with the following publications: (PMID: 11810272, 18700895, 25487149, 15556094, 20236128, 22883975, 29874871, 25637381, 9026534, 8535447, 11857755, 11139254, 15199436, 21310417, 27680772, 15523646, 25682026, 16159606, 22698793, 23375686, 26036859, 27765764, 23680767, 24507775, 31447099, 32220565, 32719484, 32041611, 33303402, 33740630, 34037665, 22859806, 30270091, 31345425, 37443404, 10559517, 34662886, 35177841, 37409534, 29284604)
Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation	RCV000172963	SCV000540819	likely pathogenic	Hypercholesterolemia, familial, 1	2016-11-05	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000775070	SCV000544697	pathogenic	Familial hypercholesterolemia	2024-01-22	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 482 of the LDLR protein (p.Asp482Asn). This variant is present in population databases (rs139624145, gnomAD 0.009%). This missense change has been observed in individuals with hypercholesterolemia (PMID: 8535447, 16389549, 20236128, 21310417, 23375686). This variant is also known as p.Asp461Asn. ClinVar contains an entry for this variant (Variation ID: 161284). 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%. This variant disrupts the p.Asp482 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16389549, 20236128, 21310417). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille	RCV000172963	SCV000583832	pathogenic	Hypercholesterolemia, familial, 1	2017-03-30	criteria provided, single submitter	clinical testing
Fundacion Hipercolesterolemia Familiar	RCV000172963	SCV000607600	likely pathogenic	Hypercholesterolemia, familial, 1	2016-03-01	criteria provided, single submitter	research
Iberoamerican FH Network	RCV000172963	SCV000748149	likely pathogenic	Hypercholesterolemia, familial, 1	2016-03-01	criteria provided, single submitter	research
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	RCV000172963	SCV000839981	likely pathogenic	Hypercholesterolemia, familial, 1	2017-05-11	criteria provided, single submitter	clinical testing	The c.1444G>A (p.Asp482Asn) variant in the LDLR gene has been reported in patients with hypercholesterolemia [PMID 8535447, 23375686, 20236128, 16159606, 21326404; legacy name 461]. This variant was observed in five heterozygous individuals in the ExAC population database (http://exac.broadinstitute.org/variant/19-11224296-G-A). Aspartate at position 482 of the LDLR protein is conserved in mammals and while not clinically validated, computer-based algorithms (SIFT and Polyphen-2) predict this p.Asp482Asn change to be deleterious. This c.1444G>A (p.Asp482Asn) variant is thus classified as likely pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000775070	SCV000909171	pathogenic	Familial hypercholesterolemia	2023-06-07	criteria provided, single submitter	clinical testing	This missense variant (also known as p.Asp461Asn in the mature protein) replaces aspartic acid with asparagine at codon 482 in the LDLR type B repeat 2 of the EGF precursor homology 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). To our knowledge, functional studies have not been reported for this variant. This LDLR variant has been reported in over 40 heterozygous individuals affected with familial hypercholesterolemia (PMID: 8535447, 10559517, 15523646, 16389549, 21310417, 20236128, 23375686, 33740630, 34037665; Color internal data) and is a recurrent variant among Irish individuals affected with familial hypercholesterolemia (PMID: 15523646). This variant has also been observed in compound heterozygous state with a known pathogenic LDLR variant in two individuals affected with severe homozygous familial hypercholesterolemia, a phenotype expected of having two deleterious LDLR variants (PMID: 30270091). It has been shown that this variant segregates with disease in three affected individuals in one family (PMID: 8535447). This variant has been identified in 11/282680 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Different variants affecting the same codon (p.Asp482Tyr, p.Asp482His and p.Asp482Gly), are considered to be disease-causing (ClinVar variation ID: 251845, 251844 and 251846), suggesting that aspartic acid at this position is important for LDLR protein function. Based on the available evidence, this variant is classified as Pathogenic.
Illumina Laboratory Services, Illumina	RCV000172963	SCV000914825	pathogenic	Hypercholesterolemia, familial, 1	2017-09-11	criteria provided, single submitter	clinical testing	Across a selection of the available literature, the LDLR c.1444G>A (p.Asp482Asn) variant has been identified in a heterozygous state in 36 cases with familial hypercholesterolemia (Taylor et al. 2010; Martin et al. 2016; Braenne et al. 2016). Control data are unavailable for this variant, which is reported at a frequency of 0.000087 in the European (non-Finnish) population of the Genome Aggregation Database. Based on the evidence, the p.Asp482Asn variant is classified as pathogenic for familial hypercholesterolemia. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000775070	SCV000917587	pathogenic	Familial hypercholesterolemia	2018-09-05	criteria provided, single submitter	clinical testing	Variant summary: LDLR c.1444G>A (p.Asp482Asn) results in a conservative amino acid change located in the LDLR class B repeat of 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 4e-05 in 277372 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in LDLR causing Familial Hypercholesterolemia (4e-05 vs 0.0013), allowing no conclusion about variant significance. c.1444G>A has been reported in the literature in multiple individuals affected with Familial Hypercholesterolemia (Bochmann_2001, Bunn_2002, Fouchier_2001, Graham_1999, Graham_2005, Martin_2016, Ward_1995). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven ClinVar submissions from other clinical diagnostic laboratories (evaluation after 2014) cite the variant as likely pathogenic/pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Institute of Human Genetics, University of Leipzig Medical Center	RCV000172963	SCV001251401	likely pathogenic	Hypercholesterolemia, familial, 1	2019-10-16	criteria provided, single submitter	clinical testing
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000172963	SCV001423103	likely pathogenic	Hypercholesterolemia, familial, 1	2020-01-22	criteria provided, single submitter	curation	The p.Asp482Asn (sometimes called p.Asp461Asn) variant in LDLR has been reported in at least 24 individuals (including 4 Czech, 3 German, 1 Norwegian, 1 Italian, and 1 Dutch individuals) with Familial Hypercholesterolemia, segregated with disease in 5 affected relatives from 2 families (PMID: 26036859, 22698793, 9026534, 15199436, 11857755, 16159606, 21310417, 11139254, 11810272), and has been identified in 0.008526% (11/129018) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs139624145). 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 as a VUS, a likely pathogenic variant, and a pathogenic variant in ClinVar (Variation ID: 161284). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PS4, PP1_Moderate, PP3 (Richards 2015).
Brunham Lab, Centre for Heart and Lung Innovation, University of British Columbia	RCV000172963	SCV001432632	likely pathogenic	Hypercholesterolemia, familial, 1	2019-05-11	criteria provided, single submitter	research
Knight Diagnostic Laboratories, Oregon Health and Sciences University	RCV002051677	SCV001448811	likely pathogenic	Hypercholesterolemia	2018-12-03	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000414235	SCV001715490	pathogenic	not provided	2022-11-08	criteria provided, single submitter	clinical testing	PP1, PP3, PM2_supporting, PM3, PM5, PS4
Revvity Omics, Revvity	RCV000172963	SCV002017120	pathogenic	Hypercholesterolemia, familial, 1	2022-10-28	criteria provided, single submitter	clinical testing
AiLife Diagnostics, AiLife Diagnostics	RCV000414235	SCV002502837	likely pathogenic	not provided	2022-01-05	criteria provided, single submitter	clinical testing
MGZ Medical Genetics Center	RCV000172963	SCV002581854	likely pathogenic	Hypercholesterolemia, familial, 1	2022-08-17	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002390311	SCV002701523	likely pathogenic	Cardiovascular phenotype	2023-12-26	criteria provided, single submitter	clinical testing	The p.D482N variant (also known as c.1444G>A), located in coding exon 10 of the LDLR gene, results from a G to A substitution at nucleotide position 1444. The aspartic acid at codon 482 is replaced by asparagine, an amino acid with highly similar properties. This alteration (also described as legacy p.D461N) has been identified in multiple individuals with familial hypercholesterolemia (FH) (Br&aelig;nne I et al. Eur. J. Hum. Genet., 2016 Feb;24:191-7; Webb JC et al. J. Lipid Res., 1996 Feb;37:368-81; Ward AJ et al. Hum. Mutat., 1995;6:254-6; Bochmann H et al. Hum. Mutat., 2001;17:76-7; Taylor A et al. Clin. Genet., 2010 Jun;77:572-80; Wang J et al. Arterioscler. Thromb. Vasc. Biol., 2016 12;36:2439-2445; Laurie AD et al. Atheroscler Suppl, 2004 Dec;5:13-5; Ho CK et al. Scott Med J, 2012 Aug;57:148-51; Hooper AJ et al. Atherosclerosis, 2012 Oct;224:430-4). It has been reported to co-segregate with disease in one family (Br&aelig;nne I et al. Eur J Hum Genet. 2016;24(2):191-7). One study has demonstrated <2% of normal LDL-R activity in an individual with this alteration and a 21 base pair deletion in exon 4 of LDLR (Webb JC et al. J Lipid Res. 1996;37(2):368-81). Another study has reported the p.D482N variant and a second LDLR variant (p.D266E, c.798T>A) in an individual with coronary heart disease (Bochmann H et al. Hum. Mutat., 2001;17:76-7). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV000172963	SCV002787866	pathogenic	Hypercholesterolemia, familial, 1	2021-10-22	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000172963	SCV004822461	pathogenic	Hypercholesterolemia, familial, 1	2024-01-08	criteria provided, single submitter	clinical testing	This missense variant (also known as p.Asp461Asn in the mature protein) replaces aspartic acid with asparagine at codon 482 in the LDLR type B repeat 2 of the EGF precursor homology 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). To our knowledge, functional studies have not been reported for this variant. This LDLR variant has been reported in over 40 heterozygous individuals affected with familial hypercholesterolemia (PMID: 8535447, 10559517, 15523646, 16389549, 21310417, 20236128, 23375686, 33740630, 34037665; Color internal data) and is a recurrent variant among Irish individuals affected with familial hypercholesterolemia (PMID: 15523646). This variant has also been observed in compound heterozygous state with a known pathogenic LDLR variant in two individuals affected with severe homozygous familial hypercholesterolemia, a phenotype expected of having two deleterious LDLR variants (PMID: 30270091). It has been shown that this variant segregates with disease in three affected individuals in one family (PMID: 8535447). This variant has been identified in 11/282680 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Different variants affecting the same codon (p.Asp482Tyr, p.Asp482His and p.Asp482Gly), are considered to be disease-causing (ClinVar variation ID: 251845, 251844 and 251846), suggesting that aspartic acid at this position is important for LDLR protein function. Based on the available evidence, this variant is classified as Pathogenic.
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	RCV000775070	SCV005045750	pathogenic	Familial hypercholesterolemia	2021-05-12	criteria provided, single submitter	clinical testing	The c.1444G>A (p.Asp482Asn) variant in LDLR gene, that encodes for low density lipoprotein receptor, has been identified in numerous unrelated individuals (>35) who fulfill the clinical criteria of Familial Hypercholesterolemia (FH) (PMID: 8535447, 10559517, 16389549, 21310417, 20236128, 23375686, 16159606, 22698793, 15199436, 11857755). This variant has also been reported in homozygous/compound heterozygous states in individuals with severe FH (PMID: 30270091, 9026534). This variant was found to segregate with disease in both heterozygous state (PMID: 26036859) and compound heterozygous state (with severe FH, PMID: 9026534). In-silico computational prediction tools suggest that this variant may have deleterious effect on the protein function (REVEL score: 0.945). This variant is found to be rare (11/282680, 0.00003891) in the general population database (gnomAD) and interpreted as likely pathogenic/pathogenic by multiple submitters in the ClinVar database (ClinVar ID: 161284). Other amino acid substitutions at the same codon (p.Asp482Tyr, p.Asp482His, p.Asp482Gly) have been classified as likely pathogenic in ClinVar (ClinVar ID: 251845, 251844, 251846). Therefore, the c.1444G>A (p.Asp482Asn) variant in LDLR gene is classified as pathogenic.
CSER _CC_NCGL, University of Washington	RCV002051677	SCV000190305	uncertain significance	Hypercholesterolemia	2014-06-01	no assertion criteria provided	research
Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital	RCV000172963	SCV000268616	pathogenic	Hypercholesterolemia, familial, 1	2008-07-22	no assertion criteria provided	clinical testing
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	RCV000172963	SCV000606428	pathogenic	Hypercholesterolemia, familial, 1		no assertion criteria provided	research
Natera, Inc.	RCV000775070	SCV001460278	pathogenic	Familial hypercholesterolemia	2020-09-16	no assertion criteria provided	clinical testing
GenomeConnect, ClinGen	RCV000775070	SCV002075084	not provided	Familial hypercholesterolemia		no assertion provided	phenotyping only	Variant interpreted as Pathogenic and reported on 09-10-2018 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.