ClinVar Miner

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

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Total submissions: 13
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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 Health, Inc 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; 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

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