ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.259T>G (p.Trp87Gly) (rs121908025)

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Total submissions: 14
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000844748 SCV000271387 pathogenic Homozygous familial hypercholesterolemia 2015-12-21 criteria provided, single submitter clinical testing The p.Trp87Gly variant in LDLR is a well-established pathogenic variant for fami lial hypercholesterolemia (Leitersdorf 1990, Jensen 1996, Vohl 1997, Tybjaerg-Ha nsen 2005, Futema 2013), and is a known founder mutation in the French Canadian population where it has been reported in >400 individuals with FH, including >15 homozygous individuals (Vohl 1997). It has also been identified in 7/126722Euro pean chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broad institute.org; dbSNP rs121908025); however, this frequency is low enough to be c onsistent with the frequency of FH in the general population. Additionally, in v itro functional studies provide some evidence that the p.Trp87Gly variant may im pact protein function (Leitersdorf 1990). In summary, this variant meets our cri teria to be classified as pathogenic for FH in an autosomal dominant manner base d upon its identification in a large number of affected individuals and low freq uency in controls. ACMG/AMP Criteria applied: PS4; PM3; PM2_Supporting; PP3; PS3 _Supporting.
Invitae RCV000776466 SCV000285027 pathogenic Familial hypercholesterolemia 2019-08-05 criteria provided, single submitter clinical testing This sequence change replaces tryptophan with glycine at codon 87 of the LDLR protein (p.Trp87Gly). The tryptophan residue is highly conserved and there is a large physicochemical difference between tryptophan and glycine. This variant is clearly defined as a familial hypercholesterolemia causative allele (PMID: 2318961, 12553167, 16542394). It is a founder mutation in the Dutch population, and is common in individuals of European ancestry. This variant is also known as p.W66G in the literature. ClinVar contains an entry for this variant (Variation ID: 3685). Experimental studies have shown that this missense change leads to an LDL receptor protein that is unable to properly bind LDL (PMID: 8098448). For these reasons, this variant has been classified as Pathogenic.
LDLR-LOVD, British Heart Foundation RCV000003870 SCV000294560 likely pathogenic Familial hypercholesterolemia 1 2016-03-25 criteria provided, single submitter literature only
Robarts Research Institute,Western University RCV000003870 SCV000484716 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 RCV000003870 SCV000503120 likely pathogenic Familial hypercholesterolemia 1 2016-12-16 criteria provided, single submitter clinical testing subjects mutated among 2600 FH index cases screened = 9 , family members = 7 with co-segregation / frequently associated with c.1975A>C, p.Thr659Pro (2 index cases), Subnormal LDLR activity / Software predictions: Damaging
Molecular Genetics Laboratory,Centre for Cardiovascular Surgery and Transplantation RCV000003870 SCV000540721 likely pathogenic Familial hypercholesterolemia 1 2016-11-05 criteria provided, single submitter clinical testing
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille RCV000003870 SCV000583644 pathogenic Familial hypercholesterolemia 1 2017-03-30 criteria provided, single submitter clinical testing
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute RCV000622852 SCV000740415 likely pathogenic not provided 2017-07-11 criteria provided, single submitter clinical testing
Color RCV000776466 SCV000912015 pathogenic Familial hypercholesterolemia 2018-01-29 criteria provided, single submitter clinical testing Pathogenic variant based on current evidence: This missense variant (also known as p.Trp66Gly in the mature protein) is located in the second LDLR type A repeat of 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. Experimental studies have demonstrated that the variant protein showed reduced LDL binding (PMID: 8645371, 10735631). This variant has been identified in over 500 individuals affected with familial hypercholesterolemia (PMID: 8098448, 9272705, 12553167, 16542394, 2318961). This variant is common in individuals of European descent and is considered a founder mutation in the French-Canadian population (PMID: 9272705). Homozygous individuals have shown much higher LDL-C levels than heterozygous individuals (PMID: 8098448). This variant has been identified in 8/277232 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on available evidence, this variant is classified as Pathogenic.
Institute of Human Genetics, University of Leipzig Medical Center RCV000003870 SCV001428736 likely pathogenic Familial hypercholesterolemia 1 2020-02-03 criteria provided, single submitter clinical testing
Brunham Lab, Centre for Heart and Lung Innovation,University of British Columbia RCV000003870 SCV001432641 pathogenic Familial hypercholesterolemia 1 2019-03-13 criteria provided, single submitter research
OMIM RCV000003870 SCV000024035 pathogenic Familial hypercholesterolemia 1 1994-04-01 no assertion criteria provided literature only
Cardiovascular Genetics Laboratory,PathWest Laboratory Medicine WA - Fiona Stanley Hospital RCV000003870 SCV000268547 pathogenic Familial hypercholesterolemia 1 2008-12-18 no assertion criteria provided clinical testing
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde,Academisch Medisch Centrum RCV000003870 SCV000606051 pathogenic Familial hypercholesterolemia 1 no assertion criteria provided research

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