ClinVar Miner

Submissions for variant NM_000527.4(LDLR):c.523G>A (p.Asp175Asn) (rs121908033)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
LDLR-LOVD, British Heart Foundation RCV000003924 SCV000294768 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 RCV000003924 SCV000503175 likely pathogenic Familial hypercholesterolemia 1 2016-12-16 criteria provided, single submitter clinical testing subject mutated among 2600 FH index cases screened = 1, family member =1 /FH-Afrikaner-3 / Software predictions: Damaging
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille RCV000003924 SCV000583693 pathogenic Familial hypercholesterolemia 1 2017-03-30 criteria provided, single submitter clinical testing
Robarts Research Institute,Western University RCV000003924 SCV000782949 likely pathogenic Familial hypercholesterolemia 1 2018-01-02 criteria provided, single submitter clinical testing
Color RCV000775043 SCV000909140 pathogenic Familial hypercholesterolemia 2018-08-13 criteria provided, single submitter clinical testing Pathogenic variant based on current evidence: This missense variant (also known as p.Asp154Asn in the mature protein and as FH Afrikaner-3) is located in the fourth LDLR type A repeat of the ligand binding domain of the LDLR protein. Computational prediction tools and conservation analyses suggest that this variant may impact the protein function. Computational splicing tools suggest that this variant may not impact the RNA splicing. Experimental functional studies have shown that this variant causes significant defect in the LDLR activity (PMID: 7773731). This variant has been reported in numerous Afrikaner individuals affected with familial hypercholesterolemia and is thought to be a founder mutation in that population (PMID: 2799589, 9727745). This variant is rare in the general population and has been identified in 2/246152 chromosomes by the Genome Aggregation Database (gnomAD). Based on available evidence, this variant is classified as Pathogenic.
Invitae RCV000775043 SCV000951227 pathogenic Familial hypercholesterolemia 2018-11-19 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with asparagine at codon 175 of the LDLR protein (p.Asp175Asn). 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 observed in individuals with familial combined hyperlipidemia, familial hypercholesterolemia (FH) and has been shown to segregate with disease in FH families (PMID: 26342331, 2799589, 3430554, 2565980, 7773731, 24014831). This variant is also known as FH Afrikaner-3, FH3 and p.Asp154Asn in the literature. ClinVar contains an entry for this variant (Variation ID: 3726). Experimental studies have shown that this missense change causes a deleterious effect on LDL binding ability and reduced LDLR cell surface expression (PMID: 7773731). For these reasons, this variant has been classified as Pathogenic.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute RCV000003924 SCV000987518 pathogenic Familial hypercholesterolemia 1 criteria provided, single submitter clinical testing
OMIM RCV000003924 SCV000024089 pathogenic Familial hypercholesterolemia 1 1991-12-01 no assertion criteria provided literature only
Cardiovascular Genetics Laboratory,PathWest Laboratory Medicine WA - Fiona Stanley Hospital RCV000003924 SCV000268568 pathogenic Familial hypercholesterolemia 1 2015-01-09 no assertion criteria provided clinical testing
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde,Academisch Medisch Centrum RCV000003924 SCV000606147 pathogenic Familial hypercholesterolemia 1 no assertion criteria provided research

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