ClinVar Miner

Submissions for variant NM_001195798.2(LDLR):c.2416dup (p.Val806fs) (rs773618064)

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Total submissions: 13
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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 2018-09-07 criteria provided, single submitter clinical testing The c.2416dupG variant in the LDLR gene, also reported as c.785insG, c.2411insG, and c.2416_2417dinsG due to alternate nomenclature, has been identified in multiple individuals from various ethnic backgrounds with a diagnosis of FH (Ekström et al., 1998; Nobe et al., 1999; Fouchier et al., 2001; Liguori et al., 2001; Yu et al., 2002; Kuhrová et al., 2002; Miyake et al., 2009; Ajmal et al., 2010; Dušková 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). Ajmal et al. (2010) reported the variant segregated with disease across three generations in a large Pakistani family. Consanguinity was noted in this family, and one individual who was homozygous for the c.2416dupG variant showed more severe clinical findings, such as a total cholesterol level above 900 mg/dl and xanthomas (Ajmal et al, 2010). Additionally, the c.2416dupG variant was identified in three homozygous siblings with severe presentations of FH (Setia et al., 2016). Segregation with elevated total and/or LDL cholesterol was also reported by Nobe et al. (1999) in at least three relatives from a Utah kindred. The c.2416dupG variant has been observed in 6/246,154 global alleles (0.002%) in large population cohorts (Lek et al., 2016). The c.2416dupG variant causes a shift in reading frame starting at codon valine 806, changing it to a glycine, and creating a premature stop codon at position 11 of the new reading frame, denoted p.Val806GlyfsX11. This pathogenic variant is expected to result in either an abnormal, truncated protein product or loss of protein from this allele through nonsense-mediated mRNA decay. Other downstream frameshift variants in the LDLR gene have been reported in Human Gene Mutation Database in association with hypercholesterolemia (Stenson et al., 2014), and loss of function is a known mechanism of disease for this gene.
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 2018-12-19 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.
Integrated Genetics/Laboratory Corporation of America 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.

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