ClinVar Miner

Submissions for variant NM_000527.4(LDLR):c.418G>A (p.Glu140Lys) (rs748944640)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge RCV000238418 SCV000322897 likely pathogenic Familial hypercholesterolemia 2016-03-01 criteria provided, single submitter research 0/100 healthy control individuals; 0/60 healthy control individuals; 0/190 non-FH alleles
Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies,APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix RCV000238418 SCV000503154 likely pathogenic Familial hypercholesterolemia 2016-12-16 criteria provided, single submitter clinical testing subjects mutated among 2600 FH index cases screened = 5 , family members = 2 with co-segregation / FH Philippine / Software predictions: Damaging
Color RCV000775038 SCV000909135 pathogenic Familial hypercholesterolemias 2018-03-23 criteria provided, single submitter clinical testing Pathogenic variant based on current evidence: This variant (also known as p.Glu119Lys in the mature protein as well as FH-Philippines, FH Durban-2) is a missense variant located in the third LDLR type A repeat in the ligand binding 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. An experimental study has shown that this variant results in a significantly reduced LDLR activity in fibroblasts from a heterozygous hypercholesterolemia patient (PMID: 1301956). Fibroblasts from a compound heterozygous hypercholesterolemia subject showed LDLR protein instability with reduced internalization and degradation (PMID: 8347689). While this variant is rare in the general population (0/277264 chromosomes by the Genome Aggregation Database (gnomAD)), it has been reported in 10+ individuals diagnosed with familial hypercholesterolemia (PMID:1301956, 11668627, 23375686, 21722902,, 15359125, 21310417, 18718593, 25962062, 11668640, 10532689, 19446849, 8347689). A different missense substitution at this codon, p.Glu140Asp, is considered to be deleterious. Based on available evidence, this variant is classified as Pathogenic.
Fundacion Hipercolesterolemia Familiar RCV000238418 SCV000607454 likely pathogenic Familial hypercholesterolemia 2016-03-01 criteria provided, single submitter research
Iberoamerican FH Network RCV000238418 SCV000748038 likely pathogenic Familial hypercholesterolemia 2016-03-01 criteria provided, single submitter research
Invitae RCV000238418 SCV000544698 pathogenic Familial hypercholesterolemia 2016-12-16 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 140 of the LDLR protein (p.Glu140Lys). 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 reported in multiple individuals and families affected with familial hypercholesterolemia (PMID: 1301956, 23375686, 21722902, 11668627, 15359125, 21310417, 18718593, 25962062, 11668640, 10532689, 19446849, 8347689) and individuals with suspected familial hypercholesterolemia (PMID: 17539906, 26343872). This variant is also known in the literature as p.Glu119Lys. ClinVar contains an entry for this variant (Variation ID: 251213). Experimental studies have shown that this missense change resulted in a reduced LDR activity in fibroblasts (PMID: 1301956). Skin fibroblasts from an affected individual with this variant as a compound heterozygous with a different variant in LDLR showed LDLR protein instability with reduced internalization and degradation (PMID: 8347689). A different missense substitution at this codon (p.Glu140Asp) has been determined to be pathogenic (PMID: 11754108, Invitae database). This suggests that the glutamic acid residue is critical for LDLR protein function and that other missense substitutions at this position may also be pathogenic. For these reasons, this variant has been classified as Pathogenic.
LDLR-LOVD, British Heart Foundation RCV000238418 SCV000294698 likely pathogenic Familial hypercholesterolemia 2016-03-25 criteria provided, single submitter literature only
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde,Academisch Medisch Centrum RCV000238418 SCV000606111 pathogenic Familial hypercholesterolemia no assertion criteria provided research
Laboratory of Genetics and Molecular Cardiology,University of São Paulo RCV000238418 SCV000588499 likely pathogenic Familial hypercholesterolemia 2016-03-01 criteria provided, single submitter research
Robarts Research Institute,Western University RCV000238418 SCV000484695 likely pathogenic Familial hypercholesterolemia criteria provided, single submitter clinical testing
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille RCV000238418 SCV000583674 pathogenic Familial hypercholesterolemia 2017-03-30 criteria provided, single submitter clinical testing

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