Submissions for variant NM_000527.5(LDLR):c.542C>G (p.Pro181Arg) (rs557344672)

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
LDLR-LOVD, British Heart Foundation	RCV000237262	SCV000294785	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	RCV000237262	SCV000503179	likely benign	Familial hypercholesterolemia 1	2016-12-16	criteria provided, single submitter	clinical testing	subject mutated among 2600 FH index cases screened = 1 / Software predictions: Conflicting
Molecular Genetics Laboratory,Centre for Cardiovascular Surgery and Transplantation	RCV000237262	SCV000540742	uncertain significance	Familial hypercholesterolemia 1	2016-11-05	criteria provided, single submitter	clinical testing
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille	RCV000237262	SCV000583701	likely pathogenic	Familial hypercholesterolemia 1	2017-03-30	criteria provided, single submitter	clinical testing
Integrated Genetics/Laboratory Corporation of America	RCV000161959	SCV000697237	uncertain significance	not provided	2016-03-15	criteria provided, single submitter	clinical testing	Variant summary: The c.542C>G affects a non-conserved nucleotide, resulting in an amino acid change, Pro to Arg. 3/4 in-silico tools (SNPs&GO not captured here due to low reliability index) predict this variant to be damaging. This variant was found in 7/131378 control chromosomes including the broad and large populations of ExAC at a frequency of 0.0000533, which does not exceed the predicted maximum expected allele frequency for a pathogenic LDLR variant (0.0012508). This variant has been reported in many FH patients/families with both co-segregation of variant with disease as well as lack of co-segregation observed (Garcia-Garcia_ 2001 and Garcia-Garcia _2011). In vitro functional studies showed that variant of interest altered LDLR precursor processing to the mature form, however, the protein activity was normal (Garcia-Garcia _2011) and showed comparable levels of cellular LDL-uptake to wild type (Thormaehlen_2015), suggesting a possible lack of functional effect which needs to be further clarified. Considering all, there is not enough evidence to conclude on either the pathogenicity or neutral effect of this variant. Therefore, this variant has been classified as a "Variant of Uncertain Significance (VUS)," until additional information becomes available.
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	RCV000237262	SCV000839992	likely pathogenic	Familial hypercholesterolemia 1	2018-04-25	criteria provided, single submitter	clinical testing	This c.542C>G (p.Pro181Arg) variant in the LDLR gene has been reported in multiple familial hypercholesterolaemia patients [PMID: 11600564, 11754108, 16250003, 23375686] than that observed as extremely low in general population according to gnomad database. Functional studies showed impairment of precursor LDLR with reduced penetrance associated with this variant [PMID: 21868016]. Multiple in silico predictions suggest this proline to arginine is deleterious. Based upon above evidences, c.542C>G (p.Pro181Arg) variant in the LDLR gene is classified as likely pathogenic.
Color	RCV001181335	SCV001346460	uncertain significance	Familial hypercholesterolemia	2020-03-12	criteria provided, single submitter	clinical testing
Dept. of Genetics and Pharmacogenomics, Merck Research Labs	RCV000161959	SCV000189534	not provided	not provided		no assertion provided	in vitro
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde,Academisch Medisch Centrum	RCV000237262	SCV000606153	pathogenic	Familial hypercholesterolemia 1		no assertion criteria provided	research