Submissions for variant NM_000527.5(LDLR):c.2054C>T (p.Pro685Leu)

Total submissions: 19

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine	RCV000844731	SCV000271386	pathogenic	Homozygous familial hypercholesterolemia	2015-12-21	criteria provided, single submitter	clinical testing	The p.Pro685Leu variant in LDLR, also described as p.Pro664Leu in the literature , has been reported in >40 individuals with familial hypercholesterolemia (FH), segregated with disease in >40 affected relatives from at least 4 families, and was identified in the homozygous state in at least 10 individuals with FH (Berto lini 2013, Sharifi 2016, Medeiros 2010,Rubinsztein 1992, Soutar 1989, Soutar 199 1, Thormaehlen 2015, Van Der Graaf 2011). This variant has also been reported by other clinical laboratories in Clinvar (Variation ID 3702) and was identified i n 6/126656 European chromosomes by the Genome Aggregation Database (gnomAD, http ://gnomad.broadinstitute.org; dbSNP rs28942084). However, this frequency is low enough to be consistent with the frequency of FH in the general population. In v itro functional studies provide some evidence that the p.Pro685Leu variant may i mpact protein function (Knight 1989, Rubinsztein 1992, Thormaehlen 2015). In sum mary, this variant meets criteria to be classified as pathogenic for familial hy percholesterolemia in an autosomal dominant manner based upon presence in multip le affected individuals, segregation studies, low frequency in controls and func tional evidence. ACMG/AMP Criteria applied: PS4, PP1_Strong, PM2, PS3_Supporting .
LDLR-LOVD, British Heart Foundation	RCV000003891	SCV000295846	likely pathogenic	Familial hypercholesterolemia 1	2016-03-25	criteria provided, single submitter	literature only
Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge	RCV000003891	SCV000322997	pathogenic	Familial hypercholesterolemia 1	2016-03-01	criteria provided, single submitter	research	0/200 non-FH alleles
Robarts Research Institute,Western University	RCV000003891	SCV000484689	likely pathogenic	Familial hypercholesterolemia 1		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	RCV000003891	SCV000503454	likely pathogenic	Familial hypercholesterolemia 1	2016-12-16	criteria provided, single submitter	clinical testing	subjects mutated among 2600 FH index cases screened = 25 (1 homozygote) , family members = 22 with co-segregation / previously described in association with FH/software prediction damaging
Molecular Genetics Laboratory,Centre for Cardiovascular Surgery and Transplantation	RCV000003891	SCV000540854	likely pathogenic	Familial hypercholesterolemia 1	2016-11-05	criteria provided, single submitter	clinical testing
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille	RCV000003891	SCV000583924	pathogenic	Familial hypercholesterolemia 1	2017-03-30	criteria provided, single submitter	clinical testing
Laboratory of Genetics and Molecular Cardiology, University of São Paulo	RCV000003891	SCV000588630	pathogenic	Familial hypercholesterolemia 1	2016-03-01	criteria provided, single submitter	research
Fundacion Hipercolesterolemia Familiar	RCV000003891	SCV000607670	pathogenic	Familial hypercholesterolemia 1	2016-03-01	criteria provided, single submitter	research
Invitae	RCV000775085	SCV000627025	pathogenic	Familial hypercholesterolemia	2019-12-13	criteria provided, single submitter	clinical testing	This sequence change replaces proline with leucine at codon 685 of the LDLR protein (p.Pro685Leu). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and leucine. This variant is present in population databases (rs28942084, ExAC 0.01%). This variant has been reported in several individuals affected with familial hypercholesterolemia and has been found to segregate with the disease in multiple families (PMID: 11031227, 15359125, 18718593, 21382890, 23155708, 23375686, 23669246, 2726768). This variant is also known as p.Pro664Leu in the literature. This variant has been reported in individuals in the Universal Mutation Database (PMID: 12124988) and has an entry in ClinVar (Variation ID: 3702). Experimental studies have shown that this missense change inhibits LDL-uptake in cultured lymphocytes (PMID: 19013141). For these reasons, this variant has been classified as Pathogenic.
Iberoamerican FH Network	RCV000003891	SCV000748105	pathogenic	Familial hypercholesterolemia 1	2016-03-01	criteria provided, single submitter	research
Fulgent Genetics,Fulgent Genetics	RCV000003891	SCV000894179	pathogenic	Familial hypercholesterolemia 1	2018-10-31	criteria provided, single submitter	clinical testing
Color	RCV000775085	SCV000909189	pathogenic	Familial hypercholesterolemia	2020-04-08	criteria provided, single submitter	clinical testing
Integrated Genetics/Laboratory Corporation of America	RCV000775085	SCV001372293	pathogenic	Familial hypercholesterolemia	2020-06-10	criteria provided, single submitter	clinical testing	Variant summary: LDLR c.2054C>T (p.Pro685Leu) results in a non-conservative amino acid change located in the EGF-like domain (IPR000742) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.8e-05 in 251236 control chromosomes. c.2054C>T has been extensively reported in the literature in multiple individuals affected with Familial Hypercholesterolemia (example, Tichy_2012, Bertolini_2013, Soutar_1989, Futema_2013). These data indicate that the variant is very likely to be associated with disease. Several publications report experimental evidence evaluating an impact on LDL-receptor activity (example, Bertolini_2013, Bertolini_1999, Knight_1989). The most pronounced variant effect results in 10%-<30% of normal activity. Twelve clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic (n=9)/likely pathogenic (n=3). Based on the evidence outlined above, the variant was classified as pathogenic.
Brunham Lab, Centre for Heart and Lung Innovation,University of British Columbia	RCV000003891	SCV001432556	pathogenic	Familial hypercholesterolemia 1	2019-01-21	criteria provided, single submitter	research
OMIM	RCV000003891	SCV000024056	pathogenic	Familial hypercholesterolemia 1	1992-12-01	no assertion criteria provided	literature only
Dept. of Genetics and Pharmacogenomics, Merck Research Labs	RCV000162007	SCV000189582	not provided	not provided		no assertion provided	in vitro
Cardiovascular Genetics Laboratory,PathWest Laboratory Medicine WA - Fiona Stanley Hospital	RCV000003891	SCV000268656	pathogenic	Familial hypercholesterolemia 1	2010-04-13	no assertion criteria provided	clinical testing
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde,Academisch Medisch Centrum	RCV000003891	SCV000606588	pathogenic	Familial hypercholesterolemia 1		no assertion criteria provided	research