ClinVar Miner

Submissions for variant NM_000527.4(LDLR):c.530C>T (p.Ser177Leu) (rs121908026)

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Total submissions: 16
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
LDLR-LOVD, British Heart Foundation RCV000003871 SCV000294773 likely pathogenic Familial hypercholesterolemia 2016-03-25 criteria provided, single submitter literature only
Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge RCV000003871 SCV000322901 pathogenic Familial hypercholesterolemia 2016-03-01 criteria provided, single submitter research 0/190 non-FH alleles, 0/32 normolipidemic individuals; 0/60 healthy control individuals
Robarts Research Institute,Western University RCV000003871 SCV000484761 likely pathogenic Familial hypercholesterolemia criteria provided, single submitter clinical testing
Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies,APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix RCV000003871 SCV000503176 likely pathogenic Familial hypercholesterolemia 2016-12-16 criteria provided, single submitter clinical testing subjects mutated among 2600 FH index cases screened = 2 , family members = 3 with co-segregationFH-Puerto-Rico, 2% LDLR Activity / Software predictions: Damaging
Molecular Genetics Laboratory,Centre for Cardiovascular Surgery and Transplantation RCV000003871 SCV000540741 likely pathogenic Familial hypercholesterolemia 2016-11-05 criteria provided, single submitter clinical testing
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille RCV000003871 SCV000583695 pathogenic Familial hypercholesterolemia 2017-03-30 criteria provided, single submitter clinical testing
Laboratory of Genetics and Molecular Cardiology,University of São Paulo RCV000003871 SCV000588505 pathogenic Familial hypercholesterolemia 2016-03-01 criteria provided, single submitter research
Fundacion Hipercolesterolemia Familiar RCV000003871 SCV000607470 pathogenic Familial hypercholesterolemia 2016-03-01 criteria provided, single submitter research
GeneDx RCV000161958 SCV000617503 pathogenic not provided 2017-10-19 criteria provided, single submitter clinical testing The S177L variant in the LDLR gene has been reported previously in the homozygous and heterozygous states, in association with Familial Hypercholesterolemia (Hobbs et al., 1989; Górski et al., 1998; Setia et al., 2016). The S177L variant is also known as the FH Puerto Rico allele because it is the most common disease-causing variant among people of Puerto Rican ancestry (Hobbs et al., 1989). The S177L variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). The S177L variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs within LDL-receptor class A 4 domain, at a position that is conserved across species. Enzyme analysis on fibroblasts from homozygous affected individuals show significantly reduced LDLR activity and in vitro studies show the S177L variant is associated with significantly reduced LDL uptake (Hobbs et al., 1992; Thormaehlen et al., 2015). Missense variants in nearby residues (D172Y, D172N, D172H, D172G, D172E, D172E, C173R, C173G, C173Y, C173W, D175N, D175Y, D175E, G176V, D178N, D178H, D178Y, D178G, D178V, D178E, E179K, E179G, P181R, P181L, C173W) have been reported in the Human Gene Mutation Database in association with Familial Hypercholesterolemia (Stenson et al., 2014), supporting the functional importance of this region of the protein. We interpret S177L as a pathogenic variant.
Invitae RCV000588687 SCV000627040 pathogenic Familial hypercholesterolemias 2018-12-04 criteria provided, single submitter clinical testing This sequence change replaces serine with leucine at codon 177 of the LDLR protein (p.Ser177Leu). The serine residue is highly conserved and there is a large physicochemical difference between serine and leucine. This variant is present in population databases (rs121908026, ExAC 0.002%). This variant has been reported in several individuals affected with familial hypercholesterolemia (PMID: 15241806, 17765246, 22698793, 25487149, 25647241, 2760205). ClinVar contains an entry for this variant (Variation ID: 3686). Experimental studies have shown that this missense change reduces the ability of the LDLR protein to bind LDL (PMID: 25647241, 2760205). For these reasons, this variant has been classified as Pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000588687 SCV000697236 pathogenic Familial hypercholesterolemias 2016-07-19 criteria provided, single submitter clinical testing Variant summary: The LDLR c.530C>T (p.Ser177Leu) variant involves the alteration of a conserved nucleotide. Ser177 is a highly conserved amino acid across species, and 4/4 in silico tools predict a damaging outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was found in 1/121078 control chromosomes at a frequency of 0.0000083, which does not exceed the estimated maximal expected allele frequency of a pathogenic LDLR variant (0.0012508). This variant has been reported in numerous patients heterozygously or homozygously. Functional studies showed this variant with defective maturation and LDL metabolism. Taken together, this variant is classified as pathogenic.
Fulgent Genetics,Fulgent Genetics RCV000003871 SCV000894167 pathogenic Familial hypercholesterolemia 2018-10-31 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000826198 SCV000967748 pathogenic Familial hypercholesterolemia - homozygous 2018-02-07 criteria provided, single submitter clinical testing The p.Ser177Leu variant in LDLR (also described as p.Ser156Leu in the literatur e) has been reported in several individuals with familial hypercholesterolemia ( FH): In at least 15 in the heterozygous state (Schuster 1993, Kuhrova 2002, Bour bon 2008, Tichy 2012, Jannes 2015, Thormaehlen 2015, Sharifi 2016), 1 with homoz ygous FH (Hobbs 1989), and 2 in the compound heterozygous state (Jannes 2015, Ku balska 2008) and has also been reported by other clinical laboratories in ClinVa r (Variation ID 3686). The variant segregated with disease in at least 9 affecte d relatives from 2 families (Hobbs 1992, Schuster 1993). However, not all family members that carried the variant presented with high cholesterol levels (Hobbs 1989). In vitro functional studies provide some evidence that the p.Ser177Leu va riant may impact protein function (Hobbs 1989, Kubalska 2008, Thormaehlen 2015). This variant has been identified in 2/30782 South Asian and 1/17246 of East Asi an chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadin; dbSNP rs121908026). This frequency is low enough to be consistent w ith the frequency of FH in the general population. Computational prediction tool s and conservation analysis suggest that the p.Ser177Leu variant may impact the protein. In summary, this variant meets criteria to be classified as pathogenic for familial hypercholesterolemia in an autosomal dominant manner based upon pre sence in multiple affected individuals, segregation studies, low frequency in th e general population and functional and computation evidence. ACMG/AMP Criteria applied (Richards 2015): PS4_strong, PP1_strong, PM2, PS3_supporting, PP3.
OMIM RCV000003871 SCV000024036 pathogenic Familial hypercholesterolemia 1993-02-01 no assertion criteria provided literature only
Dept. of Genetics and Pharmacogenomics, Merck Research Labs RCV000161958 SCV000189533 not provided not provided no assertion provided in vitro
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde,Academisch Medisch Centrum RCV000003871 SCV000606148 pathogenic Familial hypercholesterolemia no assertion criteria provided research

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