ClinVar Miner

Submissions for variant NM_000527.4(LDLR):c.1729T>C (p.Trp577Arg) (rs879255000)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
LDLR-LOVD, British Heart Foundation RCV000237252 SCV000295618 likely pathogenic Familial hypercholesterolemia 1 2016-03-25 criteria provided, single submitter literature only
Robarts Research Institute,Western University RCV000237252 SCV000484705 likely pathogenic Familial hypercholesterolemia 1 criteria provided, single submitter clinical testing
Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies,APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix RCV000237252 SCV000503398 likely pathogenic Familial hypercholesterolemia 1 2016-12-16 criteria provided, single submitter clinical testing subject mutated among 2600 FH index cases screened = 2 , family members = 3 with co-segregation / Other mutation at same codon/software prediction damaging
Invitae RCV000791446 SCV000544666 pathogenic Familial hypercholesterolemia 2018-08-20 criteria provided, single submitter clinical testing This sequence change replaces tryptophan with arginine at codon 577 of the LDLR protein (p.Trp577Arg). The tryptophan residue is highly conserved and there is a moderate physicochemical difference between tryptophan and arginine. This variant is not present in population databases (ExAC no frequency). This variant has been reported as a common cause of familial hypercholesterolemia in Turkey, although it has also been described in other populations. It has been reported in the homozygous and heterozygous state in several affected individuals, being found to segregate with the disease in at least one family (PMID: 11013454, 12436241, 15823276, 17347910, 18339137, 22528129, 28126585, 27919346). This variant is also known as p.Trp556Arg in the literature. 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. Variants that disrupt the p.Trp577 amino acid residue in LDLR have been observed in affected individuals (PMID: 8697568, 9180246, 11810272, 25378237). 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.
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille RCV000237252 SCV000583870 likely pathogenic Familial hypercholesterolemia 1 2017-03-30 criteria provided, single submitter clinical testing
Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge RCV000237252 SCV000599386 pathogenic Familial hypercholesterolemia 1 2016-03-01 criteria provided, single submitter curation
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde,Academisch Medisch Centrum RCV000237252 SCV000606500 pathogenic Familial hypercholesterolemia 1 no assertion criteria provided research

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