ClinVar Miner

Submissions for variant NM_000527.4(LDLR):c.1774G>A (p.Gly592Arg) (rs763147599)

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Total submissions: 4
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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 RCV000417321 SCV000503411 likely pathogenic Familial hypercholesterolemia 1 2016-12-16 criteria provided, single submitter clinical testing subjects mutated among 2600 FH index cases screened = 2 / Other mutation at same codon/software prediction damaging
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille RCV000417321 SCV000583882 pathogenic Familial hypercholesterolemia 1 2017-03-30 criteria provided, single submitter clinical testing
Color RCV001178326 SCV001342731 uncertain significance Familial hypercholesterolemia 2019-09-20 criteria provided, single submitter clinical testing
Invitae RCV001178326 SCV001399560 uncertain significance Familial hypercholesterolemia 2019-09-16 criteria provided, single submitter clinical testing This sequence change replaces glycine with arginine at codon 592 of the LDLR protein (p.Gly592Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is present in population databases (rs763147599, ExAC 0.02%). This variant has been observed in an individual affected with familial hypercholesterolemia (PMID: 27932355). This variant is also known as c.1393G>A (p.Gly465Arg) in the literature. ClinVar contains an entry for this variant (Variation ID: 373769). 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. This variant disrupts the p.Gly592 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been observed in individuals with LDLR-related conditions (PMID: 15864114,20663204, 21310417, 26238499, 23375686, 21925044), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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