ClinVar Miner

Submissions for variant NM_000527.4(LDLR):c.1069G>A (p.Glu357Lys) (rs879254781)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
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 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
Color RCV000775054 SCV000909154 likely pathogenic Familial hypercholesterolemias 2018-08-18 criteria provided, single submitter clinical testing Likely Pathogenic variant based on current evidence: This missense variant (also known as E366K in the mature protein and FH Paris-7) changes a highly conserved glutamic acid residue to lysin in the EGF-like repeat B of the EGF precursor homology domain of the LDLR protein. Computational prediction tools and conservation analyses suggest that this variant may have deleterious impact on the protein function. Computational splicing tools suggest that this variant may not impact the RNA splicing. Experimental functional study has shown that this variant may cause defect in protein transport or recycling (PMID: 1301956). While this variant is rare in the general population (0/277264 chromosomes in the Genome Aggregation Database (gnomAD)), it has been reported in over 10 individuals diagnosed with familial hypercholesterolemia (PMID: 1301956, 10735632, 11810272, 20506408, 21382890, 23833242). Based on available evidence this variant is classified as Likely Pathogenic.
Iberoamerican FH Network RCV000237189 SCV000748095 uncertain significance Familial hypercholesterolemia 2016-03-01 criteria provided, single submitter research
Invitae RCV000775054 SCV000963893 likely pathogenic Familial hypercholesterolemias 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.
LDLR-LOVD, British Heart Foundation RCV000237189 SCV000295202 likely pathogenic Familial hypercholesterolemia 2016-03-25 criteria provided, single submitter literature only
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde,Academisch Medisch Centrum RCV000237189 SCV000606318 pathogenic Familial hypercholesterolemia no assertion criteria provided research
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille RCV000237189 SCV000583785 pathogenic Familial hypercholesterolemia 2017-03-30 criteria provided, single submitter clinical testing

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