Submissions for variant NM_000527.5(LDLR):c.1845+2T>C

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
LDLR-LOVD, British Heart Foundation	RCV000237150	SCV000295701	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	RCV000237150	SCV000503424	pathogenic	Hypercholesterolemia, familial, 1	2016-12-16	criteria provided, single submitter	clinical testing	subject mutated among 2600 FH index cases screened = 1
Laboratory of Genetics and Molecular Cardiology, University of São Paulo	RCV000237150	SCV000588613	pathogenic	Hypercholesterolemia, familial, 1	2016-03-01	criteria provided, single submitter	research
Invitae	RCV000819649	SCV000960320	pathogenic	Familial hypercholesterolemia	2023-10-11	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 12 of the LDLR gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in LDLR are known to be pathogenic (PMID: 20809525, 28645073). This variant is present in population databases (rs778408161, gnomAD 0.0009%). Disruption of this splice site has been observed in individuals with hypercholesterolemia (PMID: 7583548, 26927322). ClinVar contains an entry for this variant (Variation ID: 252070). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000819649	SCV002041586	pathogenic	Familial hypercholesterolemia	2021-11-01	criteria provided, single submitter	clinical testing	Variant summary: LDLR c.1845+2T>C is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 5` splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4e-06 in 251462 control chromosomes (gnomAD). c.1845+2T>C has been reported in the literature in multiple individuals affected with Familial Hypercholesterolemia (e.g. Maruyama_1995, Hori_2019, Tada_2020). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submitters (evaluation after 2014) cite the variant as pathogenic (n=3) and likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as pathogenic.
Ambry Genetics	RCV002411097	SCV002717069	pathogenic	Cardiovascular phenotype	2018-06-25	criteria provided, single submitter	clinical testing	The c.1845+2T>C intronic pathogenic mutation results from a T to C substitution two nucleotides after coding exon 12 in the LDLR gene. This mutation, also described as FH Niigata, has been reported in familial hypercholesterolemia (FH) and myocardial infraction (MI) cohorts (Hobbs HH et al. Hum. Mutat., 1992;1:445-66; Maruyama T et al. Arterioscler. Thromb. Vasc. Biol., 1995 Oct;15:1713-8; Funahashi T et al. J. Intern. Med., 1996 Feb;239:187-90; Miyake Y et al. Atherosclerosis, 2009 Mar;203:153-60; Tada H et al. J Clin Lipidol, 2018 Dec;12:397-402.e2). In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as a disease-causing mutation.
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	RCV000237150	SCV000606538	pathogenic	Hypercholesterolemia, familial, 1		no assertion criteria provided	research