ClinVar Miner

Submissions for variant NM_000527.4(LDLR):c.501C>A (p.Cys167Ter) (rs752596535)

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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
LDLR-LOVD, British Heart Foundation RCV000211619 SCV000294744 pathogenic Familial hypercholesterolemia 1 2016-03-25 criteria provided, single submitter literature only
Robarts Research Institute,Western University RCV000211619 SCV000484746 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 RCV000211619 SCV000503169 pathogenic Familial hypercholesterolemia 1 2016-12-16 criteria provided, single submitter clinical testing subjects mutated among 2600 FH index cases screened = 6 , family members = 4 with co-segregation
Molecular Genetics Laboratory,Centre for Cardiovascular Surgery and Transplantation RCV000211619 SCV000540736 pathogenic Familial hypercholesterolemia 1 2016-11-05 criteria provided, single submitter clinical testing
Invitae RCV000589737 SCV000544686 pathogenic Familial hypercholesterolemia 2018-11-15 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Cys167*) in the LDLR gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been reported in the literature in several unrelated individuals with familial hypercholesterolemia (PMID: 7616128, 10208479, 12406975, 21382890, 22698793, 26892515, 27765764). This variant is also known as Cys146X in the literature. ClinVar contains an entry for this variant (Variation ID: 200918). Loss-of-function variants in LDLR are known to be pathogenic (PMID: 20809525). For these reasons, this variant has been classified as Pathogenic.
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille RCV000211619 SCV000583687 pathogenic Familial hypercholesterolemia 1 2017-03-30 criteria provided, single submitter clinical testing
Laboratory of Genetics and Molecular Cardiology, University of São Paulo RCV000211619 SCV000588503 pathogenic Familial hypercholesterolemia 1 2016-03-01 criteria provided, single submitter research
Integrated Genetics/Laboratory Corporation of America RCV000589737 SCV000697234 pathogenic Familial hypercholesterolemia 2016-12-20 criteria provided, single submitter clinical testing Variant summary: The LDLR c.501C>A (p.Cys167X) variant, alternatively also known as C146X, results in a premature termination codon, predicted to cause a truncated or absent LDLR protein due to nonsense mediated decay (NMD), which are commonly known mechanisms for disease. If NMD is escaped, this variant is expected truncate LDLR class A and B repeats, cysteine-rich domain, EGF-like calcium-binding domain, and EGF-like domain (InterPro). Truncations downstream of this position have been classified as pathogenic by our laboratory and others (e.g. p.Cys143X, p.Cys276X, p.Arg350X, etc.). This variant is absent in 121248 control chromosomes. In literature, this variant is reported as pathogenic variant and is found in many FH patients. The variant is particularly a frequent mutation in Dutch FH patients. Multiple clinical diagnostic laboratories/reputable databases have classified this variant as pathogenic/likely pathogenic. Taken together, this variant is classified as Pathogenic.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000825616 SCV000966968 pathogenic Familial hypercholesterolemia - homozygous 2018-02-09 criteria provided, single submitter clinical testing The p.Cys167X variant in LDLR (also described as p.Cys146X in the literature) ha s been reported in the heterozygous state in >10 individuals with familial hyper cholesterolemia (FH), segregated with disease in one affected relative from one family (Lombardi 1995, Heath 1999, Fouchier 2001, Bodamer 2002, van der Graaf 20 11, Tichy 2012, Sharifi 2016) and was absent from large population studies. Addi tionally, this variant has been reported by other clinical laboratories in ClinV ar (Variation ID: 200918). This nonsense variant leads to a premature terminatio n codon at position 167, which is predicted to lead to a truncated or absent pro tein. Heterozygous loss of function of the LDLR gene is an established disease m echanism in FH. In summary, this variant meets our criteria to be classified as pathogenic for familial hypercholesterolemia in an autosomal dominant manner bas ed upon predicted impact to the protein, presence in multiple affected individua ls and absence in the general population. ACMG/AMP Criteria applied (Richards 20 15): PVS1, PS4_Moderate, PM2.
Cardiovascular Genetics Laboratory,PathWest Laboratory Medicine WA - Fiona Stanley Hospital RCV000211619 SCV000268565 pathogenic Familial hypercholesterolemia 1 2009-04-17 no assertion criteria provided clinical testing
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde,Academisch Medisch Centrum RCV000211619 SCV000606136 pathogenic Familial hypercholesterolemia 1 no assertion criteria provided research
Stanford Center for Inherited Cardiovascular Disease,Stanford University RCV000786348 SCV000925130 pathogenic not provided no assertion criteria provided provider interpretation Genetic testing: The patient had genetic testing for the familial LDLR mutation that was first identified in her brother, p.167*. at Ambry Genetics. Results reported on July 5, 2016 showed that the following variant was identified. Ambry classifies this variant as pathogenic. Given the loss of function nature of this variant and sufficient case data in other individuals we consider this variant pathogenic and we do feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). This variant was previously identified in an affected family member of Ms. Gose. An individual with a missense variant at this codon is reported in Clinvar. Lombardi P et al. J. Lipid Res. 1995;36(4):860-7 reported this variant as it's other name (p.Cys146*) and Heath KE et al. Atherosclerosis 1999;143(1):41-54 reported this variant in a 27 Y male with FH. This variant is not reported in ExAC.

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