ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.313+2dup

dbSNP: rs875989897
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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
LDLR-LOVD, British Heart Foundation RCV000211687 SCV000294607 likely 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 RCV000211687 SCV000503135 likely pathogenic Hypercholesterolemia, familial, 1 2016-12-16 criteria provided, single submitter clinical testing subject mutated among 2600 FH index cases screened = 1, family member=1
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille RCV000211687 SCV000583656 pathogenic Hypercholesterolemia, familial, 1 2017-03-30 criteria provided, single submitter clinical testing
Fundacion Hipercolesterolemia Familiar RCV000211687 SCV000607442 likely pathogenic Hypercholesterolemia, familial, 1 2016-03-01 criteria provided, single submitter research
Iberoamerican FH Network RCV000211687 SCV000748083 likely pathogenic Hypercholesterolemia, familial, 1 2016-03-01 criteria provided, single submitter research
Invitae RCV001054512 SCV001218830 pathogenic Familial hypercholesterolemia 2024-01-24 criteria provided, single submitter clinical testing This sequence change falls in intron 3 of the LDLR gene. It does not directly change the encoded amino acid sequence of the LDLR protein. RNA analysis indicates that this variant induces altered splicing and likely results in a shortened protein product. This variant is present in population databases (no rsID available, gnomAD 0.006%). This variant has been observed in individuals with familial hypercholesterolemia (PMID: 15241806, 21990180). ClinVar contains an entry for this variant (Variation ID: 226317). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of exon 3, but is expected to preserve the integrity of the reading-frame (PMID: 21990180). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV002321828 SCV002607539 pathogenic Cardiovascular phenotype 2018-12-21 criteria provided, single submitter clinical testing The c.313+2dupT intronic pathogenic mutation, results from a duplication of a T nucleotide two nucleotide positions after coding exon 3 of the LDLR gene. This alteration has been detected as homozgyous in multiple individuals with clinically confirmed homozygous familial hypercholesterolemia (HoFH) (Sánchez-Hernández RM et al. Circ Cardiovasc Genet, 2016 Dec;9:504-510; Alonso R et al. J Clin Lipidol Apr;10:953-961) and as heterozygous in multiple individuals with familial hypercholesterolemia (FH) (Bañares VG et al. J Clin Lipidol Feb;11:524-531; Gabová D et al. Physiol Res, 2017 Mar;66:75-84; Mozas P et al. Hum. Mutat., 2004 Aug;24:187). In one functional study, authors showed that this mutation impacts ligand binding and results in the skipping of in-frame exon 3 at the mRNA level (Etxebarria A et al. Hum. Mutat., 2012 Jan;33:232-43). In addition, a different alteration with the same molecular splicing impact, c.313+6T>C, has been detected in individuals with FH and has been shown at the mRNA level to induce exon 3 skipping (Bourbon M et al. Atherosclerosis, 2008 Feb;196:633-42). (Bourbon M et al. J. Med. Genet., 2009 May;46:352-7). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital RCV000211687 SCV000268555 pathogenic Hypercholesterolemia, familial, 1 2013-07-04 no assertion criteria provided clinical testing
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum RCV000211687 SCV000606076 pathogenic Hypercholesterolemia, familial, 1 no assertion criteria provided research

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