ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.1069G>A (p.Glu357Lys) (rs879254781)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
LDLR-LOVD, British Heart Foundation RCV000237189 SCV000295202 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 RCV000237189 SCV000503294 pathogenic Familial hypercholesterolemia 1 2016-12-16 criteria provided, single submitter clinical testing subjects mutated among 2600 FH index cases screened = 12 , family members = 11 with co-segregation / FH-Paris-7 / Software predictions: Damaging
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille RCV000237189 SCV000583785 pathogenic Familial hypercholesterolemia 1 2017-03-30 criteria provided, single submitter clinical testing
Iberoamerican FH Network RCV000237189 SCV000748095 uncertain significance Familial hypercholesterolemia 1 2016-03-01 criteria provided, single submitter research
Color RCV000775054 SCV000909154 likely pathogenic Familial hypercholesterolemia 2019-03-22 criteria provided, single submitter clinical testing
Invitae RCV000775054 SCV000963893 likely pathogenic Familial hypercholesterolemia 2018-10-17 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 357 of the LDLR protein (p.Glu357Lys). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in several individuals affected with familial hypercholesterolemia or with clinical features of this condition (PMID: 1301956, 28502510, 10735632, 15199436, Invitae). This variant is also known as E336K in the literature. ClinVar contains an entry for this variant (Variation ID: 251649). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant disrupts the p.Glu357 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been observed in affected individuals (PMID: 16250003), which suggests that this may be a clinically significant amino acid residue. 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.
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde,Academisch Medisch Centrum RCV000237189 SCV000606318 pathogenic Familial hypercholesterolemia 1 no assertion criteria provided research
Broad Institute Rare Disease Group,Broad Institute RCV000775054 SCV001422598 likely pathogenic Familial hypercholesterolemia 2020-01-22 no assertion criteria provided curation The p.Glu357Lys variant in LDLR has been reported in at least 11 individuals with familial hypercholesterolemia, segregated with disease in 6 affected relatives from 1 family (PMID: 15199436), and was absent from large population studies. This variant has also been reported in ClinVar as having conflicting interpretations of pathogenicity (Variation ID: 251649). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PM2, PP1_moderate, PP3, PS4_supporting (Richards 2015).

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