Total submissions: 19
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Laboratory for Molecular 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- |
RCV000003891 | SCV000295846 | likely pathogenic | Familial hypercholesterolemia 1 | 2016-03-25 | criteria provided, single submitter | literature only | |
Cardiovascular Research Group, |
RCV000003891 | SCV000322997 | pathogenic | Familial hypercholesterolemia 1 | 2016-03-01 | criteria provided, single submitter | research | 0/200 non-FH alleles |
Robarts Research Institute, |
RCV000003891 | SCV000484689 | likely pathogenic | Familial hypercholesterolemia 1 | criteria provided, single submitter | clinical testing | ||
Centre de Génétique Moléculaire et Chromosomique, |
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, |
RCV000003891 | SCV000540854 | likely pathogenic | Familial hypercholesterolemia 1 | 2016-11-05 | criteria provided, single submitter | clinical testing | |
U4M - |
RCV000003891 | SCV000583924 | pathogenic | Familial hypercholesterolemia 1 | 2017-03-30 | criteria provided, single submitter | clinical testing | |
Laboratory of Genetics and Molecular Cardiology, |
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, |
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, |
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. |
RCV000162007 | SCV000189582 | not provided | not provided | no assertion provided | in vitro | ||
Cardiovascular Genetics Laboratory, |
RCV000003891 | SCV000268656 | pathogenic | Familial hypercholesterolemia 1 | 2010-04-13 | no assertion criteria provided | clinical testing | |
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, |
RCV000003891 | SCV000606588 | pathogenic | Familial hypercholesterolemia 1 | no assertion criteria provided | research |