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

Total submissions: 13

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	2019-12-27	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	RCV000775041	SCV000909138	pathogenic	Familial hypercholesterolemia	2018-08-14	criteria provided, single submitter	clinical testing	Pathogenic variant based on current evidence: This missense variant (also known as p.Asp147Asn in the mature protein) is located in the fourth LDLR type A repeat of the ligand binding domain of the LDLR protein. Computational prediction tools and conservation analyses suggest that this variant may have deleterious impact on the protein function. Computational splicing tools suggest that this variant may not impact the RNA splicing. Experimental 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). While this variant is rare in the general population (2/246122 chromosomes in the Genome Aggregation Database (gnomAD)), it has been reported in over 10 individuals diagnosed with familial hypercholesterolemia (PMID: 15556094, 16205024, 16389549, 17955342, 22859806, 23669246, 27784735, 28379029). Based on available evidence this variant is classified as Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine	RCV000825592	SCV000966934	likely pathogenic	Homozygous familial hypercholesterolemia	2017-10-31	criteria provided, single submitter	clinical testing	The p.Asp168Asn variant in LDLR has been reported in at least 8 individuals with familial hypercholesterolemia (FH) and in 2 individuals with early-onset myocar dial infarction (Day et al. 1997, Lee et al. 1998, Punzalan et al. 2005, Do et a l., 2015, ClinVar: Variation ID 183136). In vitro functional studies provide som e evidence that the p.Asp168Asn variant may cause a decrease in LDL uptake and b inding (Etxebarria 2015). This variant has also been identified in 2/111620 Euro pean chromosomes by the Genome Aggregation Database (GnomAD, http://gnomad.broad institute.org; dbSNP rs200727689). Computational prediction tools and conservati on analysis suggest that the p.Asp168Asn variant may impact the protein. Additio nally, other variants at this position have been reported in association with FH in the Human Gene Mutation Database (HGMD; Stenson et al. 2017). In summary, al though additional studies are required to fully establish its clinical significa nce, the p.Asp168Asn variant is likely pathogenic for autosomal dominant FH. ACM G/AMP Criteria applied (Richards 2015): PS4_Moderate, PS3_Supporting, PM2, PP3.
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).
Integrated Genetics/Laboratory Corporation of America	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.
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