Submissions for variant NM_000527.5(LDLR):c.502G>A (p.Asp168Asn) (rs200727689)

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
LDLR-LOVD, British Heart Foundation	RCV000211669	SCV000294746	likely pathogenic	Familial hypercholesterolemia 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	Familial hypercholesterolemia 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	Familial hypercholesterolemia 1	2016-11-05	criteria provided, single submitter	clinical testing
Fundacion Hipercolesterolemia Familiar	RCV000211669	SCV000607464	pathogenic	Familial hypercholesterolemia 1	2016-03-01	criteria provided, single submitter	research
Invitae	RCV000775041	SCV000627039	pathogenic	Familial hypercholesterolemia	2020-09-20	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid with asparagine at codon 168 of the LDLR protein (p.Asp168Asn). The aspartic acid residue is highly conserved and there is a small physicochemical difference between aspartic acid and asparagine. This variant is present in population databases (rs200727689, ExAC 0.003%). This variant has been reported in numerous unrelated individuals affected with familial hypercholesterolemia (PMID: 9259195, 9678702, 12124988, 15556094, 16205024, 19007590, 22859806, 27784735). This variant is also known as p.Asp147Asn in the literature. ClinVar contains an entry for this variant (Variation ID: 183136). Experimental studies have shown that this missense change causes a significantly reduced affinity to LDL (PMID: 25545329, 25647241). For these reasons, this variant has been classified as Pathogenic.
Color Health, Inc	RCV000775041	SCV000909138	pathogenic	Familial hypercholesterolemia	2021-02-02	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; Color internal data), including a homozygous individual with severe phenotype (PMID: 27784735). This variant has been identified in 2/246122 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, Partners HealthCare 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	Familial hypercholesterolemia 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	Familial hypercholesterolemia 1	2019-03-10	criteria provided, single submitter	research
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	RCV000775041	SCV001434984	likely pathogenic	Familial hypercholesterolemia	2018-08-06	criteria provided, single submitter	clinical testing	This c.502G>A (p.Asp168Asn) variant in the LDLR gene has been reported in multiple unrelated individuals with familial hypercholesterolemia (PMID 9259195, 15556094, 16205024, 19007590,22859806, 27784735) or myocardial infarction (PMID 25487149) and is extremely rare in general population. Functional studies have shown that this variant disrupts normal LDLR functionality by significantly decreasing LDL binding and LDL uptake (PMID 25545329). Based on this information, the c.502G>A (p.Asp168Asn) variant in the PCSK9 gene is classified as likely pathogenic.
Institute of Human Genetics, University of Leipzig Medical Center	RCV000211669	SCV001950090	pathogenic	Familial hypercholesterolemia 1	2021-08-24	criteria provided, single submitter	clinical testing
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	Familial hypercholesterolemia 1	2014-04-04	no assertion criteria provided	clinical testing