ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.131G>A (p.Trp44Ter) (rs267607213)

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Total submissions: 20
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Institute for Integrative and Experimental Genomics,University of Luebeck RCV000003939 SCV000212131 likely pathogenic Familial hypercholesterolemia 1 criteria provided, single submitter research
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000844726 SCV000271381 pathogenic Homozygous familial hypercholesterolemia 2015-03-23 criteria provided, single submitter clinical testing The p.Trp44X variant in LDLR has been reported in a large number (>500) of indiv iduals with hypercholesterolemia (Hobbs 1992, Huijgen 2010, Chmara 2010, Duskova 2011, Fouchier 2015). It was absent from large population studies. This nonsens e variant leads to a premature termination codon at position 44, which is predic ted to lead to a truncated or absent protein. Heterozygous loss of LDLR function is an established disease mechanism in familial hypercholesterolemia. In summar y, this variant meets our criteria to be classified as pathogenic for hyperchole sterolemia in an autosomal dominant manner (http://www.partners.org/personalized medicince/LMM) based upon the predicted impact to the protein, its presence in a large number of affected individuals, and absence from controls.
LDLR-LOVD, British Heart Foundation RCV000003939 SCV000294478 pathogenic Familial hypercholesterolemia 1 2016-03-25 criteria provided, single submitter literature only
Robarts Research Institute,Western University RCV000003939 SCV000484698 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 RCV000003939 SCV000503103 pathogenic Familial hypercholesterolemia 1 2016-12-16 criteria provided, single submitter clinical testing subjects mutated among 2600 FH index cases screened = 10 , family members = 2 with co-segregation / FH-Cincinnati-5, 2 to 5% LDLR activity
Molecular Genetics Laboratory,Centre for Cardiovascular Surgery and Transplantation RCV000003939 SCV000540718 pathogenic Familial hypercholesterolemia 1 2016-11-05 criteria provided, single submitter clinical testing
Invitae RCV000003939 SCV000544649 pathogenic Familial hypercholesterolemia 1 2017-11-14 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal at codon 44 (p.Trp44*) of the LDLR gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in LDLR are known to be pathogenic. This particular variant has been reported in the literature in multiple individuals affected with hypercholesterolemia (PMID: 1301956, 22390909, 21382890, 11668627, 22698793, 20145306, 16542394, 20506408). This variant is also known in the literature as p.W23X. For these reasons, this variant has been classified as Pathogenic.
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille RCV000003939 SCV000583633 pathogenic Familial hypercholesterolemia 1 2017-03-30 criteria provided, single submitter clinical testing ACMG Guidelines: Pathogenic (ii)
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine RCV000003939 SCV000839974 pathogenic Familial hypercholesterolemia 1 2017-09-19 criteria provided, single submitter clinical testing This c.131G>A (p.Trp44*) variant in the LDLR gene is predicted to is predicted to introduce a premature translation termination codon. This variant has been reported in multiple patients with familial hypercholesterolemia (PMID: 1301956, 8850176). The c.131G>A (p.Trp44*) variant in the LDLR gene is classified as pathogenic.
Color Health, Inc RCV000775022 SCV000909119 pathogenic Familial hypercholesterolemia 2018-08-19 criteria provided, single submitter clinical testing Pathogenic variant based on current evidence: This variant (also known as W23X in the mature protein and as FH Cincinnati-5) changes a single nucleotide in exon 2 of the LDLR gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. Loss-of-function truncation variants in the LDLR gene are known to be pathogenic (PMID: 20809525). While this variant is rare in the general population (0/277264 chromosomes in the Genome Aggregation Database (gnomAD)), it has been reported in over 60 individuals affected with hypercholesterolemia (PMID: 1301956, 11668627, 16542394, 20145306, 20506408, 21382890, 22390909, 22698793). Based on available evidence, this variant is classified as Pathogenic.
Brunham Lab, Centre for Heart and Lung Innovation,University of British Columbia RCV000003939 SCV001432627 pathogenic Familial hypercholesterolemia 1 2019-01-23 criteria provided, single submitter research
Mayo Clinic Laboratories, Mayo Clinic RCV000786354 SCV001715233 pathogenic not provided 2020-07-23 criteria provided, single submitter clinical testing PVS1, PS4, PM2, PS3_moderate, PM3_supporting
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000775022 SCV001748774 pathogenic Familial hypercholesterolemia 2021-06-28 criteria provided, single submitter clinical testing Variant summary: LDLR c.131G>A (p.Trp44X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 251254 control chromosomes. In a cross sectional ascertainment, c.131G>A has been widely reported in the literature in individuals affected with Familial Hypercholesterolemia (example, Hobbs_1992, Huijgen_2012, Luirink_2019, Dron_2020). These data indicate that the variant is likely to be associated with disease. Multiple clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
GeneDx RCV000786354 SCV001789004 pathogenic not provided 2020-10-20 criteria provided, single submitter clinical testing Not observed in large population cohorts (Lek et al., 2016); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Published functional studies demonstrate a damaging effect as this variant results in a null allele (Hobbs et al., 1992); Reported in ClinVar (ClinVar Variant ID# 3741; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 32665702, 32331935, 32719484, 32041611, 31447099, 31048103, 22390909, 26036859, 12417285, 9157944, 8645371, 8850176, 1301956, 25525159)
OMIM RCV000003939 SCV000024104 pathogenic Familial hypercholesterolemia 1 1986-10-05 no assertion criteria provided literature only
Cardiovascular Genetics Laboratory,PathWest Laboratory Medicine WA - Fiona Stanley Hospital RCV000003939 SCV000268535 pathogenic Familial hypercholesterolemia 1 2008-07-22 no assertion criteria provided clinical testing
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde,Academisch Medisch Centrum RCV000003939 SCV000606021 pathogenic Familial hypercholesterolemia 1 no assertion criteria provided research
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV000003939 SCV000733811 pathogenic Familial hypercholesterolemia 1 no assertion criteria provided clinical testing
Stanford Center for Inherited Cardiovascular Disease, Stanford University RCV000786354 SCV000925140 pathogenic not provided 2016-08-16 no assertion criteria provided provider interpretation The patient had genetic testing for the familial hypercholesterolemia panel. The test included sequencing of four genes associated with familial hypercholesterolemia: LDLR, APOB, PCSK9 and LDLRAP1. Results showed that the following variant was identified (see report below): p.Trp44* (c.131G>A) in the LDLR gene (NM_000527.4) The lab classifies this variant as pathogenic. Given sufficient case data and the loss of function nature of this variant we consider this variant pathogenic and we do feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). The variant has been seen in at least nine unrelated cases of FH (not including this patient's family). This amounts to strong case data. Some of these individuals are reported as p.W23X in the literature due to alternate transcript terminology. See PMIDs: 1301956, 22390909, 21382890, 11668627, 22698793, 20145306, 16542394, 20506408).
Clinical Genetics,Academic Medical Center RCV000786354 SCV001918524 pathogenic not provided no assertion criteria provided clinical testing

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