Submissions for variant NM_000527.5(LDLR):c.1586+1G>A

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
LDLR-LOVD, British Heart Foundation	RCV000238067	SCV000295508	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	RCV000238067	SCV000503369	likely pathogenic	Hypercholesterolemia, familial, 1	2016-12-16	criteria provided, single submitter	clinical testing	subjects mutated among 2600 FH index cases screened = 3
Laboratory of Genetics and Molecular Cardiology, University of São Paulo	RCV000238067	SCV000588593	pathogenic	Hypercholesterolemia, familial, 1	2016-03-01	criteria provided, single submitter	research
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001290569	SCV001478645	pathogenic	Familial hypercholesterolemia	2021-01-28	criteria provided, single submitter	clinical testing	Variant summary: LDLR c.1586+1G>A 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 prime 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 251100 control chromosomes. c.1586+1G>A has been reported in the literature in multiple individuals affected with Familial Hypercholesterolemia (e.g. Bertolini_2013, Tada_2020). These data indicate that the variant is very likely to be associated with disease. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Laboratory of molecular diagnosis of dyslipidemias, Università egli studi di Napoli Federico II	RCV000238067	SCV001653642	pathogenic	Hypercholesterolemia, familial, 1	2021-05-24	criteria provided, single submitter	clinical testing
Invitae	RCV001290569	SCV002230028	pathogenic	Familial hypercholesterolemia	2023-04-09	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 10 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). For these reasons, this variant has been classified as Pathogenic. Studies have shown that disruption of this splice site is associated with altered splicing resulting in multiple RNA products (PMID: 9974426). ClinVar contains an entry for this variant (Variation ID: 251905). This variant is also known as g>a+1 (ln 10). Disruption of this splice site has been observed in individuals with hypercholesterolemia (PMID: 9974426, 23375686, 30710474, 31491741, 35339733). This variant is present in population databases (rs755389753, gnomAD 0.0009%).
Ambry Genetics	RCV002401937	SCV002705979	pathogenic	Cardiovascular phenotype	2023-09-18	criteria provided, single submitter	clinical testing	The c.1586+1G>A intronic variant results from a G to A substitution one nucleotide after coding exon 10 of the LDLR gene. 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. Based on data from gnomAD, the A allele has an overall frequency of <0.001% (1/251100) total alleles studied. The highest observed frequency was 0.001% (1/113504) of European (non-Finnish) alleles. This alteration, first reported as FH Agrigento (g>a+1 In 10), was detected in the homozygous state in a child from a familial hypercholesterolemia (FH) cohort who had elevated LDL cholesterol, coronary artery disease, aortic stenosis, and <3% LDL receptor activity in fibroblasts (Bertolini, 1999). This alteration has also been detected in other FH cohorts (Liguori, 2001; Romano, 2010). This nucleotide position is highly conserved in available vertebrate species. This alteration was reported to result in abnormal splicing, leading to two abnormal mRNA products, one with an in-frame insertion of 22 amino acids, and one with an in-frame deletion of 76 amino acids in the epidermal growth factor precursor homology domain (Bertolini, 1999). In silico splice site analysis predicts that this alteration will weaken the native splice donor site. Based on the available evidence, this alteration is classified as pathogenic.
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	RCV000238067	SCV000606458	pathogenic	Hypercholesterolemia, familial, 1		no assertion criteria provided	research