ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.912C>G (p.Asp304Glu) (rs875989909)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
LDLR-LOVD, British Heart Foundation RCV000211616 SCV000295047 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 RCV000211616 SCV000503251 likely pathogenic Familial hypercholesterolemia 1 2016-12-16 criteria provided, single submitter clinical testing subject mutated among 2600 FH index cases screened = 1 / FH-Baltimore-1, 2 to 5% LDLR Activity / Software predictions: Benign
Invitae RCV000781500 SCV000544661 pathogenic Familial hypercholesterolemia 2019-07-01 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with glutamic acid at codon 304 of the LDLR protein (p.Asp304Glu). The aspartic acid residue is highly conserved and there is a small physicochemical difference between aspartic acid and glutamic acid. This variant is not present in population databases (ExAC no frequency) . This variant has been reported in several individuals affected with familial hypercholesterolemia (PMID: 1301956, 17094996). This variant is also known as p.Asp283Glu in the literature. ClinVar contains an entry for this variant (Variation ID: 226336). A different missense substitution at this codon p.Asp304Asn has been determined to be pathogenic (PMID: 17094996). This suggests that the aspartic acid residue is critical for LDLR protein function and that other missense substitutions at this position may also be pathogenic. In an experimental study, this variant was shown to reduce LDLR activity (PMID: 1301956). In summary, this is a rare missense change which has been reported in affected individuals, affects a critical residue of the protein and has been shown to affect protein function. For these reasons it has been classified as Pathogenic..
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille RCV000211616 SCV000583759 pathogenic Familial hypercholesterolemia 1 2017-03-30 criteria provided, single submitter clinical testing
Robarts Research Institute,Western University RCV000211616 SCV000782955 likely pathogenic Familial hypercholesterolemia 1 2018-01-02 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000781500 SCV000919580 pathogenic Familial hypercholesterolemia 2017-11-16 criteria provided, single submitter clinical testing Variant summary: The LDLR c.912C>G (p.Asp304Glu) variant involves the alteration of a non-conserved nucleotide that leads to the substitution of a highly conserved Asp in the ligand-binding region of the LDLR, in the class A repeat 7 domain (Interpro) where it is part of a highly conserved acidic residue motif (DXXXDXXDXXDE), corresponding to the 3rd conserved acidic residue that is involved in the proper folding of the domain through the coordinated binding of a calcium ion (Guo 2004). The variant was shown to result in a class 2B disease mechanism, i.e. causing a partial transport defect, where the LDLR protein is not properly transported from the endoplasmic reticulum to the Golgi apparatus for expression on the cell surface (Hobbs 1992). 4/5 in silico tools also predict a damaging outcome for this variant. This variant is absent in 246114 control chromosomes, but has been reported in several affected individuals (Hobbs 1992, Hooper 2012). In addition, multiple clinical diagnostic laboratories classified this variant as pathogenic/likely pathogenic. Taken together, this variant is classified as pathogenic.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000826177 SCV000967716 likely pathogenic Homozygous familial hypercholesterolemia 2018-01-19 criteria provided, single submitter clinical testing The p.Asp304Glu variant in LDLR has been reported in at least 3 individuals with familial hypercholesterolemia, two of which were compound heterozygotes (FH; Ho bbs 1992, Tosi 2007, Webb 1996). It has also been reported by other clinical lab oratories in ClinVar (Variation ID 226336) and is absent from large population s tudies. In vitro functional studies have shown that cultured fibroblasts from co mpound heterozygous carriers of the p.Asp304Glu variant have reduced LDLR activ ity (2-5% with c.2309-?_*2514+?del and 25-30% with p.Asp96Gly; Hobbs 1992, Webb 1996). In addition, other disease-causing variants (p.Asp304Asn, p.Asp304Tyr) a t this position have been reported in individuals with FH (Hobbs 1992, Do 2015, Loux 1992, Thormaehlen 2015, Tichy 2012, Vohnout 2016), suggesting changes at th is position are not tolerated. In summary, although additional studies are requi red to fully establish its clinical significance, the p.Asp304Glu variant is lik ely pathogenic. ACMG/AMP Criteria applied: PM2, PM5, PS3_Moderate, PS4_Supportin g (Richards 2015).
Cardiovascular Genetics Laboratory,PathWest Laboratory Medicine WA - Fiona Stanley Hospital RCV000211616 SCV000268588 pathogenic Familial hypercholesterolemia 1 2008-06-10 no assertion criteria provided clinical testing
Broad Institute Rare Disease Group,Broad Institute RCV000781500 SCV001422861 likely pathogenic Familial hypercholesterolemia 2020-01-22 no assertion criteria provided curation The p.Asp304Glu variant in LDLR has been reported in 1 European and 1 Australian individual with familial hypercholesterolemia (PMID: 22883975, 1301956), and was absent from large population studies. This variant has also been reported in ClinVar as pathogenic and likely pathogenic (Variation ID: 226336). In vitro functional studies provide some evidence that the p.Asp304Glu variant may slightly impact protein function (PMID: 1301956). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. Two additional likely pathogenic variants, resulting in a different amino acid change at the same position, p.Asp304Tyr and p.Asp304Asn, have been reported in association with disease in the literature and Clinvar, supporting that a change at this position may not be tolerated (PMID: 17094996, 11845603, 1301956, 9664576, 21418584, 11810272, 12436241, 22698793, 11939787, 2088165/DOI: 10.1161/CIRCGEN.118.002192/Variation ID: 251517, 3692). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PM2, PM5, PP3, PS3_supporting, PS4_supporting (Richards 2015).

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