Total submissions: 9
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
LDLR- |
RCV000211605 | SCV000294860 | likely pathogenic | Familial hypercholesterolemia 1 | 2016-03-25 | criteria provided, single submitter | literature only | |
Centre de Génétique Moléculaire et Chromosomique, |
RCV000211605 | SCV000503198 | likely pathogenic | Familial hypercholesterolemia 1 | 2016-12-16 | criteria provided, single submitter | clinical testing | subject mutated among 2600 FH index cases screened = 1 / previously described in association with FH / Software predictions: Conflicting |
Molecular Genetics Laboratory, |
RCV000211605 | SCV000540748 | likely pathogenic | Familial hypercholesterolemia 1 | 2016-11-05 | criteria provided, single submitter | clinical testing | Asp221 bind structural Ca2+. |
Invitae | RCV000791440 | SCV000544692 | pathogenic | Familial hypercholesterolemia | 2019-12-30 | criteria provided, single submitter | clinical testing | This sequence change replaces aspartic acid with asparagine at codon 221 of the LDLR protein (p.Asp221Asn). The aspartic acid residue is highly conserved and there is a small physicochemical difference between aspartic acid and asparagine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in eight individuals affected with familial hypercholesterolemia (PMID: 17094996, 11196104, 25962062, 1714262, 24075752). This variant is also known as c.661G>A, p.Asp200Asn in the literature. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). Different missense substitutions at this codon (p.Asp221Tyr and p.Asp221Gly) are reported to be deleterious and are found in patients affected with hypercholesterolemia or myocardial infarction (PMID: 1301956, 19318025, 23375686, 25647241, 25487149). This indicates that the aspartic acid residue is important for LDLR protein function. For these reasons, this variant has been classified as Pathogenic. |
Color Health, |
RCV000791440 | SCV001358758 | pathogenic | Familial hypercholesterolemia | 2019-07-21 | criteria provided, single submitter | clinical testing | |
Brunham Lab, |
RCV000211605 | SCV001432567 | pathogenic | Familial hypercholesterolemia 1 | 2019-06-05 | criteria provided, single submitter | research | |
Human Genome Sequencing Center Clinical Lab, |
RCV000791440 | SCV001435006 | pathogenic | Familial hypercholesterolemia | 2018-10-12 | criteria provided, single submitter | clinical testing | The c.661G>A (p.Asp221Asn) variant in the LDLR gene has been reported in multiple individuals with familial hypercholesterolemia (PMID: 9409298, 10090484, 11196104, 15199436, 15359125, 16250003, 17094996, 24075752, 25962062). The variant is not observed in gnomAD. The allelic change p.Asp221Tyr is an established pathogenic variant for FH. Functional studies demonstrated deleterious effect of the p.Asp221Asn variant. Multiple algorithms predicted this change to be deleterious. Therefore, the c.661G>A (p.Asp221Asn) variant in the LDLR gene is classified as pathogenic. |
Cardiovascular Genetics Laboratory, |
RCV000211605 | SCV000268576 | pathogenic | Familial hypercholesterolemia 1 | 2008-06-27 | no assertion criteria provided | clinical testing | |
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, |
RCV000211605 | SCV000606185 | pathogenic | Familial hypercholesterolemia 1 | no assertion criteria provided | research |