ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.2140G>T (p.Glu714Ter)

gnomAD frequency: 0.00001  dbSNP: rs869320652
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
SNPedia RCV000210844 SCV000267120 likely pathogenic Hypercholesterolemia, familial, 1 2016-04-03 criteria provided, single submitter literature only
LDLR-LOVD, British Heart Foundation RCV000210844 SCV000295890 pathogenic Hypercholesterolemia, familial, 1 2016-03-25 criteria provided, single submitter literature only
Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix RCV000210844 SCV000503468 pathogenic Hypercholesterolemia, familial, 1 2016-12-16 criteria provided, single submitter clinical testing subjects mutated among 2600 FH index cases screened = 5 , family members = 5
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille RCV000210844 SCV000583930 pathogenic Hypercholesterolemia, familial, 1 2017-03-30 criteria provided, single submitter clinical testing
GeneDx RCV000523095 SCV000617496 pathogenic not provided 2021-04-14 criteria provided, single submitter clinical testing Identified in at least two unrelated patients with familial hypercholesterolemia (FH) in the published literature (also reported as E693X due to alternate nomenclature) (Amsellam et al., 2002; Khera et al., 2016), and in a patient referred for testing at GeneDx.; Not observed at a significant frequency 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; Reported in ClinVar as pathogenic (ClinVar Variant ID#225183; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 27050191, 12436241, 25525159, 12124988)
Invitae RCV002229190 SCV000752420 pathogenic Familial hypercholesterolemia 2023-02-14 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 225183). This variant is also known as E693X. This premature translational stop signal has been observed in individual(s) with familial hypercholesterolemia (PMID: 12124988, 12436241). This variant is present in population databases (no rsID available, gnomAD 0.002%). This sequence change creates a premature translational stop signal (p.Glu714*) in 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 (PMID: 20809525, 28645073).
Ambry Genetics RCV002426986 SCV002730086 pathogenic Cardiovascular phenotype 2021-05-27 criteria provided, single submitter clinical testing The p.E714* pathogenic mutation (also known as c.2140G>T), located in coding exon 14 of the LDLR gene, results from a G to T substitution at nucleotide position 2140. This changes the amino acid from a glutamic acid to a stop codon within coding exon 14. This alteration, which is also known as p.E693*, has been reported in familial hypercholesterolemia (FH) cohorts (Amsellem S et al. Hum Genet, 2002 Dec;111:501-1; Khera AV et al. J Am Coll Cardiol, 2016 06;67:2578-89; Marmontel O et al. Clin Genet, 2018 07;94:132-140). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.

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