ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.2416dup (p.Val806fs)

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Total submissions: 17
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
LDLR-LOVD, British Heart Foundation RCV000238458 SCV000296001 pathogenic Familial hypercholesterolemia 1 2016-03-25 criteria provided, single submitter literature only
Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge RCV000238458 SCV000323014 pathogenic Familial hypercholesterolemia 1 2016-03-01 criteria provided, single submitter research 0/188 non-FH alleles
Robarts Research Institute,Western University RCV000238458 SCV000484801 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 RCV000238458 SCV000503487 uncertain significance Familial hypercholesterolemia 1 2016-12-16 criteria provided, single submitter clinical testing subjects mutated among 2600 FH index cases screened = 4 , family members = 2
Molecular Genetics Laboratory,Centre for Cardiovascular Surgery and Transplantation RCV000238458 SCV000540871 pathogenic Familial hypercholesterolemia 1 2016-11-05 criteria provided, single submitter clinical testing
GeneDx RCV000486216 SCV000568526 pathogenic not provided 2021-03-26 criteria provided, single submitter clinical testing Identified in multiple individuals from various ethnic backgrounds with a diagnosis of FH in the published literature, also reported as c.785insG, c.2411insG, and c.2416_2417insG due to alternate nomenclature (Ekstrm et al., 1998; Nobe et al., 1999; Fouchier et al., 2001; Liguori et al., 2001; Yu et al., 2002; Kuhrov et al., 2002; Miyake et al., 2009; Ajmal et al., 2010; Dukov et al., 2011; Bertolini et al., 2013; Jannes et al., 2015; Khera et al., 2016; Setia et al., 2016; Xiang et al., 2017; Fairoozy et al., 2017; Trinder et al., 2019); Frameshift 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; Reported in ClinVar but additional evidence is not available (ClinVar Variant ID#252330; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 23375686, 25846081, 11317362, 23535506, 11810272, 29213121, 9767373, 25461735, 11754108, 10611908, 20217239, 18718593, 27050191, 21310417, 25682442, 28235710, 12417285, 27816806, 28994502, 31491741, 31345425, 32041611, 33303402, 32770674)
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille RCV000238458 SCV000583950 pathogenic Familial hypercholesterolemia 1 2017-03-30 criteria provided, single submitter clinical testing
Laboratory of Genetics and Molecular Cardiology, University of São Paulo RCV000238458 SCV000588665 pathogenic Familial hypercholesterolemia 1 2016-03-01 criteria provided, single submitter research
Fundacion Hipercolesterolemia Familiar RCV000238458 SCV000607706 pathogenic Familial hypercholesterolemia 1 2016-03-01 criteria provided, single submitter research
Invitae RCV000780378 SCV000823681 pathogenic Familial hypercholesterolemia 2020-09-17 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Val806Glyfs*11) in the LDLR gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs773618064, ExAC 0.01%). This variant has been observed to segregate with familial hypercholesterolemia in a family, being found in individuals with this condition in both the dominant and recessive forms (PMID: 9767373, 10611908, 27816806). This variant is also known as c.785insG, 2412-6insG and c.2416_2417insG (p.Val806Glyfs*10) in the literature. ClinVar contains an entry for this variant (Variation ID: 252330). Loss-of-function variants in LDLR are known to be pathogenic (PMID: 20809525). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000780378 SCV000917581 pathogenic Familial hypercholesterolemia 2017-10-24 criteria provided, single submitter clinical testing Variant summary: The LDLR c.2416dupG (p.Val806GlyfsX11) variant results in a premature termination codon, predicted to cause a truncated or absent LDLR protein due to nonsense mediated decay, which are commonly known mechanisms for disease. This variant was found in 6/246402 control chromosomes (including gnomAD) at a frequency of 0.0000244, which does not exceed the estimated maximal expected allele frequency of a pathogenic LDLR variant (0.0012508). The 6 occurrences observed in gnomAD need to be cautiously considered because the cohort could harbor individuals with an LDLR phenotype. Multiple publications have cited the variant in affected individuals including a large consanguineous Pakistani family that segregated across multiple generations, including one homozygous affected family member with a more severe phenotype (Ajmal_2010). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Department of Human Genetics,Laborarztpraxis Dres. Walther, Weindel und Kollegen RCV000238458 SCV000987034 pathogenic Familial hypercholesterolemia 1 2019-02-21 criteria provided, single submitter clinical testing The mutation leads to the amino acid exchange valine to glycine at position 806 at protein level, as well as a premature termination of protein synthesis.The concomitant loss of LDL receptor activity has already been described in patients with hypercholesterolemia.This variant was observed in a patient with TC up to 360 mg/dl and LDL-C approx. 310 mg/dl. This mutation is therefore classified as pathogenic. PMID: 9767373, 10611908, 25846081
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000486216 SCV001134261 pathogenic not provided 2019-02-16 criteria provided, single submitter clinical testing The variant results in a shift of the reading frame, and is therefore predicted to result in the loss of a functional protein. Found in at least one symptomatic patient, and found in general population data that is consistent with pathogenicity. Moderate co-segregation with disease in affected individuals.
Color Health, Inc RCV000780378 SCV001352608 pathogenic Familial hypercholesterolemia 2018-10-01 criteria provided, single submitter clinical testing
Brunham Lab, Centre for Heart and Lung Innovation,University of British Columbia RCV000238458 SCV001432638 pathogenic Familial hypercholesterolemia 1 2019-05-10 criteria provided, single submitter research
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine RCV000780378 SCV001435013 pathogenic Familial hypercholesterolemia 2019-03-01 criteria provided, single submitter clinical testing The c.2416dupG (p.Val806Glyfs*11) variant in the LDLR gene is predicted to introduce a premature translational termination codon. This variant has been reported in multiple unrelated individuals affected with familial hypercholesterolemia (PMID 9767373, 10611908, 11754108, 12417285, 20217239) and has shown to segregate with disease in two families (PMID 10611908, 20217239). Therefore, this c.2416dupG (p.Val806Glyfs*11) variant in the LDLR gene is classified as pathogenic.
Clinical Genetics,Academic Medical Center RCV000486216 SCV001926010 pathogenic not provided no assertion criteria provided clinical testing

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