Submissions for variant NM_000527.5(LDLR):c.2390-2A>G

dbSNP: rs767790696

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
LDLR-LOVD, British Heart Foundation	RCV000238115	SCV000295983	pathogenic	Hypercholesterolemia, familial, 1	2016-03-25	criteria provided, single submitter	literature only
Invitae	RCV001828123	SCV000544639	pathogenic	Familial hypercholesterolemia	2023-06-04	criteria provided, single submitter	clinical testing	This variant is present in population databases (rs767790696, gnomAD 0.0009%). This sequence change affects an acceptor splice site in intron 16 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). Disruption of this splice site has been observed in individuals with familial hypercholesterolemia (PMID: 8141835, 10441197, 12052488, 16465405, 20145306, 21382890, 22698793). It has also been observed to segregate with disease in related individuals. 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 unknown protein product impact (PMID: 8141835). ClinVar contains an entry for this variant (Variation ID: 252313).
Fundacion Hipercolesterolemia Familiar	RCV000238115	SCV000607701	pathogenic	Hypercholesterolemia, familial, 1	2016-03-01	criteria provided, single submitter	research
Robarts Research Institute, Western University	RCV000238115	SCV000782940	pathogenic	Hypercholesterolemia, familial, 1	2018-01-02	criteria provided, single submitter	clinical testing
Brunham Lab, Centre for Heart and Lung Innovation, University of British Columbia	RCV000238115	SCV001432636	pathogenic	Hypercholesterolemia, familial, 1	2019-06-05	criteria provided, single submitter	research
Ambry Genetics	RCV002450749	SCV002737105	pathogenic	Cardiovascular phenotype	2019-01-07	criteria provided, single submitter	clinical testing	The c.2390-2A>G intronic pathogenic mutation (also known as IVS16-2A>G) results from an A to G substitution two nucleotides upstream from coding exon 17 in the LDLR gene. This alteration has been reported in multiple familial hypercholesterolemia (FH) cohorts and functional studies have shown this alteration to have an impact on splicing (Lombardi P et al. Atherosclerosis, 1993 Dec;104:117-28; Peeters AV et al. Mol. Cell. Probes, 1999 Aug;13:257-60; Alonso R et al. Clin. Biochem., 2009 Jun;42:899-903; Chmara M et al. J. Appl. Genet., 2010;51:95-106; Lind S et al. Atherosclerosis, 2002 Aug;163:399-407; van der Graaf A et al. Circulation, 2011 Mar;123:1167-73). 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	RCV000238115	SCV000606639	pathogenic	Hypercholesterolemia, familial, 1		no assertion criteria provided	research
Natera, Inc.	RCV001828123	SCV002086877	pathogenic	Familial hypercholesterolemia	2021-01-05	no assertion criteria provided	clinical testing