ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.1988-2A>G

dbSNP: rs879255101
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix RCV000417318 SCV000503448 pathogenic Hypercholesterolemia, familial, 1 2016-12-16 criteria provided, single submitter clinical testing subject mutated among 2600 FH index cases screened = 1
Department of Human Genetics, Laborarztpraxis Dres. Walther, Weindel und Kollegen RCV000417318 SCV000987016 pathogenic Hypercholesterolemia, familial, 1 2018-01-16 criteria provided, single submitter clinical testing The mutation leads to alteration of the nearly invariant dinucleotide "AG" of the 3 'splice site consensus sequence in the intron. Alteration of this dinucleotide leads to an error in the splicing of the RNA. This mutation has already been described in patients with hypercholesterolemia and is therefore classified as pathogenic. This variant was observed in a patient with TC approx. 250 mg/dl and LDL-C approx 200 mg/dl at the age of 30. PMID: 17964958, 23375686
Ambry Genetics RCV002418242 SCV002718419 likely pathogenic Cardiovascular phenotype 2021-08-04 criteria provided, single submitter clinical testing The c.1988-2A>G intronic variant results from an A to G substitution two nucleotides upstream from coding exon 14 in the LDLR gene. Alterations that disrupt the canonical splice site are expected to result in aberrant splicing. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site and will result in the creation or strengthening of a novel splice acceptor site. The resulting transcript is predicted to be in-frame and is not expected to trigger nonsense-mediated mRNAdecay; however, direct evidence is unavailable. The exact functional effect of the altered amino acid sequence is unknown; however, the impacted region is critical for protein function (Ambry internal data). This variant has been reported in individuals with hypercholesterolemia; however, clinical details were limited (Bertolini S et al. Atherosclerosis, 2013 Apr;227:342-8). This nucleotide position is highly conserved in available vertebrate species. Based on the majority of available evidence to date, this variant is likely to be pathogenic.

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