ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.1694G>T (p.Gly565Val) (rs28942082)

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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 RCV000003874 SCV000295584 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 RCV000003874 SCV000503387 pathogenic Familial hypercholesterolemia 1 2016-12-16 criteria provided, single submitter clinical testing subjects mutated among 2600 FH index cases screened = 6 , family members = 2 with co-segregation / Functional test, FH-Naples-2, 2% LDLR Activity, Other mutations at same codon / Software predictions: Damaging
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille RCV000003874 SCV000583865 pathogenic Familial hypercholesterolemia 1 2017-03-30 criteria provided, single submitter clinical testing
Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge RCV000003874 SCV000599379 pathogenic Familial hypercholesterolemia 1 2016-03-01 criteria provided, single submitter curation
Invitae RCV000791454 SCV000752407 pathogenic Familial hypercholesterolemia 2018-10-08 criteria provided, single submitter clinical testing This sequence change replaces glycine with valine at codon 565 of the LDLR protein (p.Gly565Val). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and valine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in both the homozygous and heterozygous state in several individuals affected with familial hypercholesterolemia (PMID: 2901412, 23375686, 12436241). This variant is also described in the literature as p.Gly544Val. ClinVar contains an entry for this variant (Variation ID: 3688). Experimental studies have shown that this missense change disrupts transport of LDL-receptor to the Golgi apparatus, resulting in a cell surface that lacks LDL-receptors (PMID: 2901412, 16740646). Variants that disrupt the p.Gly565 amino acid residue in LDLR have been observed in affected individuals (PMID: 27784735, 11313767). This suggests that it is a clinically significant residue, and that other variants that disrupt this residue are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV001195593 SCV001365989 likely pathogenic Homozygous familial hypercholesterolemia 2020-01-09 criteria provided, single submitter clinical testing The p.Gly565Val variant in LDLR (also described as p.Gly544Val in the literature) has been reported in the heterozygous state in at least 5 individuals and in the homozygous state in 1 individual with familial hypercholesterolemia (FH) and segregated with disease in 2 affected relatives from at least one family (ClinVar: SCV000503387.1 and SCV000583865.1, Esser 1988, Amsellem 2002). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID: 3688) and was absent from large population studies. Computational prediction tools and conservation analyses suggest that this variant may impact the protein. In vitro functional studies support an impact on protein function (Esser 1988). Additional variants involving this codon (p.Gly565Asp and p.Gly565Ala) have been identified in individuals with FH. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant FH. ACMG/AMP Criteria applied: PM2, PS4_Moderate, PP3, PS3_Supporting
OMIM RCV000003874 SCV000024039 pathogenic Familial hypercholesterolemia 1 1988-09-15 no assertion criteria provided literature only
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde,Academisch Medisch Centrum RCV000003874 SCV000606487 pathogenic Familial hypercholesterolemia 1 no assertion criteria provided research

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