ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.2475C>G (p.Asn825Lys) (rs374045590)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
LDLR-LOVD, British Heart Foundation RCV000237920 SCV000296017 likely pathogenic Familial hypercholesterolemia 1 2016-03-25 criteria provided, single submitter literature only
Robarts Research Institute,Western University RCV000237920 SCV000484701 likely pathogenic Familial hypercholesterolemia 1 criteria provided, single submitter clinical testing
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille RCV000237920 SCV000583956 pathogenic Familial hypercholesterolemia 1 2017-03-30 criteria provided, single submitter clinical testing
Invitae RCV001228564 SCV001400967 likely pathogenic Familial hypercholesterolemia 2019-08-22 criteria provided, single submitter clinical testing This sequence change replaces asparagine with lysine at codon 825 of the LDLR protein (p.Asn825Lys). The asparagine residue is highly conserved and there is a moderate physicochemical difference between asparagine and lysine. This variant is present in population databases (rs374045590, ExAC 0.003%). This variant has been observed in several individuals affected with familial hypercholesterolemia (PMID: 11668627, 18096825, 27830735, 27765764). This variant is also known in the literature as N804K. ClinVar contains an entry for this variant (Variation ID: 161265). This variant has been reported to affect LDLR protein function (PMID: 25378237). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
CSER _CC_NCGL, University of Washington RCV000148570 SCV000190283 likely pathogenic Hypercholesterolaemia 2014-06-01 no assertion criteria provided research
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde,Academisch Medisch Centrum RCV000237920 SCV000606657 pathogenic Familial hypercholesterolemia 1 no assertion criteria provided research
Broad Institute Rare Disease Group,Broad Institute RCV000237920 SCV001422630 pathogenic Familial hypercholesterolemia 1 2020-01-22 no assertion criteria provided curation The p.Asn825Lys variant in LDLR has been reported in 75 individuals (including 71 Norweigans, 2 Italian, and 1 Danish, and 1 Dutch individuals) with Familial Hypercholesterolemia, segregated with disease in 71 affected relatives from 19 families (PMID: 15199436, 11810272, 23375686, 11668627, 10532689), and has been identified in 0.001758% (2/113744) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs374045590). Please note that for diseases with clinical variability, or reduced penetrance, pathogenic variants may be present at a low frequency in the general population. This variant has also been reported likely pathogenic and pathogenic in ClinVar (Variation ID: 161265). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. One additional variant with the same amino acid change, c.2475C>A (p.Asn825Lys), has been reported pathogenic and likely pathogenic in association with disease in ClinVar and the literature, supporting that this variant is pathogenic (Variation ID: 252341). In summary, this variant meets criteria to be classified as pathogenic for Familial Hypercholesterolemia in an autosomal dominant manner based on multiple reports of individuals with disease and cosegregation with Familial Hypercholesterolemia. ACMG/AMP Criteria applied: PS4, PP1_Strong, PS1, PP3 (Richards 2015).

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