Submissions for variant NM_000527.5(LDLR):c.502G>A (p.Asp168Asn)

gnomAD frequency: 0.00001  dbSNP: rs200727689

Total submissions: 22

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
LDLR-LOVD, British Heart Foundation	RCV000211669	SCV000294746	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	RCV000211669	SCV000503170	likely pathogenic	Hypercholesterolemia, familial, 1	2016-12-16	criteria provided, single submitter	clinical testing	subjects mutated among 2600 FH index cases screened = 3 , family member = 1 with co-segregation / FH-Sephardic, 2 to 5% LDLR Activity / Software predictions: Conflicting
Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation	RCV000211669	SCV000540737	likely pathogenic	Hypercholesterolemia, familial, 1	2016-11-05	criteria provided, single submitter	clinical testing
Fundacion Hipercolesterolemia Familiar	RCV000211669	SCV000607464	pathogenic	Hypercholesterolemia, familial, 1	2016-03-01	criteria provided, single submitter	research
Labcorp Genetics (formerly Invitae), Labcorp	RCV000775041	SCV000627039	pathogenic	Familial hypercholesterolemia	2024-01-07	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 168 of the LDLR protein (p.Asp168Asn). This variant is present in population databases (rs200727689, gnomAD 0.002%). This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 9259195, 9678702, 12124988, 15556094, 16205024, 19007590, 22859806, 27784735). This variant is also known as p.Asp147Asn. ClinVar contains an entry for this variant (Variation ID: 183136). 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: 25545329, 25647241). For these reasons, this variant has been classified as Pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000775041	SCV000909138	pathogenic	Familial hypercholesterolemia	2023-03-01	criteria provided, single submitter	clinical testing	This missense variant (also known as p.Asp147Asn in the mature protein) replaces aspartic acid with asparagine at codon 168 in the fourth LDLR type A repeat of the ligand binding domain of the LDLR protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown that this variant causes a significant decrease in LDL binding and uptake, although effect is not as severe as null alleles (PMID: 25545329, 25647241). This variant has been reported in over ten individuals and families affected with familial hypercholesterolemia (PMID: 15556094, 16205024, 16389549, 17955342, 22859806, 23669246, 27784735, 28379029, 33807407, 34037665; Color internal data), including a homozygous individual with severe phenotype (PMID: 27784735). This variant has been identified in 2/251288 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Different missense variants occurring at the same amino acid position (p.Asp168His, p.Asp168Gly, p.Asp168Tyr) are known to be disease-causing (ClinVar variation ID: 251258, 251260, 251259), indicating that aspartic acid at this position is important for LDLR function. Based on available evidence, this variant is classified as Pathogenic.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000825592	SCV000966934	pathogenic	Homozygous familial hypercholesterolemia	2021-04-07	criteria provided, single submitter	clinical testing	The p.Asp168Asn variant in LDLR has been reported in the heterozygous state in at least 12 individuals (11 heterozygotes, 1 homozygote) with familial hypercholesterolemia (FH), and in 2 individuals with early-onset myocardial infarction and segregated with FH in one affected relative (Day 1997 PMID: 9259195, Lee 1998 PMID: 9678702, Punzalan 2005 PMID: 16205024, Taylor 2010 PMID: 20236128, Do 2015 PMID: 25487149, Wald 2016 PMID: 27783906, Sanchez-Hernandez 2016 PMID: 27784735). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID: 183136) and has been identified in 0.002% (2/113632) European chromosomes by the gnomAD (http://gnomad.broadinstitute.org). In vitro functional studies provide some evidence that the p.Asp168Asn variant may cause a decrease in LDL uptake and binding (Etxebarria 2015 PMID: 25545329) and computational prediction tools and conservation analyses are consistent with pathogenicity. Additionally, other variants at this position (p.Asp168His, p.Asp168Gly, p.Asp168Gln) have been reported in association with FH by multiple clinical laboratories in ClinVar. In summary, the p.Asp168Asn variant meets criteria to be classified as pathogenic for autosomal dominant FH. ACMG/AMP Criteria applied: PS4, PS3_Moderate, PM1, PM2_Supporting, PP3, PM5_Supporting.
UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill	RCV000211669	SCV001251447	likely pathogenic	Hypercholesterolemia, familial, 1		criteria provided, single submitter	research	The LDLR c.502G>A (p.D168N) variant has been previously reported in the heterozygous state in autosomal dominant familial hypercholesterolemia (PMID: 9259195; 9678702; 12124988; 15556094; 19007590; 25545329; 25647241).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000775041	SCV001339065	pathogenic	Familial hypercholesterolemia	2020-03-02	criteria provided, single submitter	clinical testing	Variant summary: LDLR c.502G>A (p.Asp168Asn) results in a conservative amino acid change located in the LDLR ligand binding domain (R4) (Etxebarria_2015) 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 8e-06 in 251288 control chromosomes (gnomAD). c.502G>A has been reported in the literature in multiple individuals affected with Familial Hypercholesterolemia (Taylor_2010, Rall_2014, Sanchez-Hernandez_2016, Wald-2016). These data indicate that the variant is very likely to be associated with disease. At least one functional study reports this variant effect results in an impaired LDL binding capacity of WT. Seven ClinVar submitters (evaluation after 2014) cite the variant as pathogenic (3x) and likely pathogenic (4x). Based on the evidence outlined above, the variant was classified as pathogenic.
Brunham Lab, Centre for Heart and Lung Innovation, University of British Columbia	RCV000211669	SCV001432608	pathogenic	Hypercholesterolemia, familial, 1	2019-03-10	criteria provided, single submitter	research
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	RCV000775041	SCV001434984	pathogenic	Familial hypercholesterolemia	2021-02-04	criteria provided, single submitter	clinical testing	The c.502G>A (p.Asp168Asn) variant in the LDLR gene is located on the exon 4 and is predicted to replace aspartic acid with asparagine at codon 168 (p.Asp168Asn). The variant has been reported in more than 10 unrelated individuals affected with familial hypercholesterolemia (PMID: 33807407, 32522009, 27783906, 27784735, 28379029, 22859806, 19007590, 16389549, 16205024, 9678702, 30293936). The p.Asp168Asn variant is located in the well-established functional domain (amino acids 105-232) critical to the protein function. Experimental study in the LDLR deficient cell line proved the negative functional impact of this variant and defective LDL binding (<70%) (PMID: 25545329). The variant has been reported in ClinVar (ID: 183136). This variant is rare in the general population according to gnomAD (2/251288). Computational prediction algorithms suggest a deleterious impact (REVEL score 0.78). Therefore, the c.502G>A (p.Asp168Asn) variant of LDLR has been classified as pathogenic.
Institute of Human Genetics, University of Leipzig Medical Center	RCV000211669	SCV001950090	pathogenic	Hypercholesterolemia, familial, 1	2021-08-24	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002336377	SCV002642995	likely pathogenic	Cardiovascular phenotype	2024-02-20	criteria provided, single submitter	clinical testing	The p.D168N variant (also known as c.502G>A), located in coding exon 4 of the LDLR gene, results from a G to A substitution at nucleotide position 502. The aspartic acid at codon 168 is replaced by asparagine, an amino acid with highly similar properties, and is located in the ligand binding region of the protein. This alteration (also referred to as D147N) has been detected in individuals from multiple familial hypercholesterolemia cohorts and in an an individual with mixed hyperlipidemia (Day IN et al. Hum Mutat. 1997;10:116-27; Lee WK et al. J Med Genet. 1998;35:573-8; Laurie AD et al. Atheroscler Suppl. 2004;5(5):13-5;Civeira F et al. J Am Coll Cardiol. 2008; Futema M et al. Atherosclerosis. 2013;229:161-8; Raal FJ et al. Lancet. 2015;385(9965):341-50; S&aacute;nchez-Hern&aacute;ndez RM et al. Circ Cardiovasc Genet. 2016;9(6):504-510). This variant has been reported to result in reduced LDL binding and uptake in vitro (Etxebarria A et al. Atherosclerosis. 2015 Feb;238(2):304-12; Thormaehlen AS et al. PLoS Genet. 2015;11(2):e1004855). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV000211669	SCV002777075	pathogenic	Hypercholesterolemia, familial, 1	2021-12-06	criteria provided, single submitter	clinical testing
GeneDx	RCV000162017	SCV003762076	pathogenic	not provided	2022-08-10	criteria provided, single submitter	clinical testing	Published functional studies demonstrate decreased receptor binding and LDL uptake compared to wild type protein (Etxebarria et al., 2015; Thormaehlen et al., 2015); Not observed at a significant frequency in large population cohorts (gnomAD); Also known as D147N; This variant is associated with the following publications: (PMID: 9259195, 30617148, 15556094, 16205024, 31447099, 25487149, 9678702, 12124988, 19007590, 25647241, 22859806, 27784735, 29874871, 28379029, 23669246, 32522009, 33807407, 32853555, 32719484, 33740630, 34037665, 33087929, 2988123, 12459547, 25545329)
Revvity Omics, Revvity	RCV000211669	SCV003827850	pathogenic	Hypercholesterolemia, familial, 1	2022-12-05	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000211669	SCV004820173	pathogenic	Hypercholesterolemia, familial, 1	2023-12-18	criteria provided, single submitter	clinical testing	This missense variant (also known as p.Asp147Asn in the mature protein) replaces aspartic acid with asparagine at codon 168 in the fourth LDLR type A repeat of the ligand binding domain of the LDLR protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown that this variant causes a significant decrease in LDL binding and uptake, although effect is not as severe as null alleles (PMID: 25545329, 25647241). This variant has been reported in over ten individuals and families affected with familial hypercholesterolemia (PMID: 15556094, 16205024, 16389549, 17955342, 22859806, 23669246, 27784735, 28379029, 33807407, 34037665; Color internal data), including a homozygous individual with severe phenotype (PMID: 27784735). This variant has been identified in 2/251288 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Different missense variants occurring at the same amino acid position (p.Asp168His, p.Asp168Gly, p.Asp168Tyr) are known to be disease-causing (ClinVar variation ID: 251258, 251260, 251259), indicating that aspartic acid at this position is important for LDLR function. Based on available evidence, this variant is classified as Pathogenic.
Dept. of Genetics and Pharmacogenomics, Merck Research Labs	RCV000162017	SCV000189620	not provided	not provided		no assertion provided	in vitro
Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital	RCV000211669	SCV000268566	pathogenic	Hypercholesterolemia, familial, 1	2014-04-04	no assertion criteria provided	clinical testing
Natera, Inc.	RCV000775041	SCV002086367	pathogenic	Familial hypercholesterolemia	2020-02-11	no assertion criteria provided	clinical testing
Zotz-Klimas Genetics Lab, MVZ Zotz Klimas	RCV000211669	SCV004041738	pathogenic	Hypercholesterolemia, familial, 1	2023-10-09	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003927531	SCV004744631	pathogenic	LDLR-related disorder	2024-07-23	no assertion criteria provided	clinical testing	The LDLR c.502G>A variant is predicted to result in the amino acid substitution p.Asp168Asn. This variant is alternatively referred to as p.Asp147Asn using legacy nomenclature. This variant and other similar variants affecting amino acid Asp168 have been reported in several unrelated patients with hypercholesterolemia (Day et al. 1997 PubMed ID: 9259195; Lee et al. 1998 PubMed ID: 9678702; Punzalan et al. 2005 PubMed ID: 16205024; Civiera et al. 2008 PubMed ID: 19007590; Etxebarria et al. 2015 PubMed ID: 25545329). This variant is reported in 0.0018% of alleles in individuals of European (non-Finnish) descent in gnomAD and is reported as pathogenic/likely pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/183136/). This variant is interpreted as pathogenic.