Submissions for variant NM_000527.5(LDLR):c.1705+1G>A

dbSNP: rs875989926

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
LDLR-LOVD, British Heart Foundation	RCV000211580	SCV000295591	likely pathogenic	Hypercholesterolemia, familial, 1	2016-03-25	criteria provided, single submitter	literature only
Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge	RCV000211580	SCV000599381	pathogenic	Hypercholesterolemia, familial, 1	2016-03-01	criteria provided, single submitter	curation
Iberoamerican FH Network	RCV000211580	SCV000748114	pathogenic	Hypercholesterolemia, familial, 1	2016-03-01	criteria provided, single submitter	research
Invitae	RCV001034672	SCV000752424	pathogenic	Familial hypercholesterolemia	2019-02-23	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in LDLR are known to be pathogenic (PMID: 20809525). Experimental studies have shown that this chance results in exon skipping and in reduced LDLR activity (PMID: 19208450). This variant was observed in individuals affected with familial hypercholesterolemia (PMID: 10532689, 20145306, 19208450, 17406740).   ClinVar contains an entry for this variant (Variation ID: 226367). This variant is not present in population databases (ExAC no frequency). This sequence change affects a donor splice site in intron 11 of the LDLR gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product.
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	RCV000211580	SCV000839976	likely pathogenic	Hypercholesterolemia, familial, 1	2018-03-27	criteria provided, single submitter	clinical testing	The c.1705+1G>A variant in the LDLR gene disrupts the canonical splice donor site in intron 11 and is predicted to result in abnormal mRNA splicing. This variant has been reported in multiple unrelated individuals with familial hypercholesterolemia (PMID: 10532689, 19318025, 20145306). The c.1705+1G>A variant in the LDLR gene is classified as likely pathogenic.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000825623	SCV000966975	pathogenic	Homozygous familial hypercholesterolemia	2018-06-11	criteria provided, single submitter	clinical testing	The c.1705+1G>A variant in LDLR has been reported in 6 Caucasian individuals wit h hypercholesterolemia (Jensen 1999, Chmara 2010, Sharifi 2016) and was absent f rom large population studies. This variant occurs in the invariant region (+/- 1 ,2) of the splice consensus sequence and is predicted to cause altered splicing leading to an abnormal or absent protein. Furthermore, other variants in the sam e splice consensus sequence have been reported in individuals with hypercholeste rolemia (c.1705+1G>C, c.1705+1G>T). In vitro functional studies of the c.1705+1G >T and the c.1705+1G>A variants provide some evidence of abnormal splicing (R?dn ingen 1999; Holla 2009). In summary, this variant meets criteria to be classifie d as pathogenic for hypercholesterolemia in an autosomal dominant manner based u pon proband counts, absence from controls, and functional impact. ACMG/AMP Crite ria applied: PVS1; PM2; PS4_Supporting; PS3_Supporting.
Ambry Genetics	RCV002408917	SCV002715538	pathogenic	Cardiovascular phenotype	2019-09-26	criteria provided, single submitter	clinical testing	The c.1705+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 11 of the LDLR gene. This alteration has been detected in several individuals with familial hypercholesterolemia (FH) (Jensen HK et al. Atherosclerosis, 1999 Oct;146:337-44; Chmara M et al. J. Appl. Genet., 2010;51:95-106; Hooper AJ et al. Atherosclerosis, 2012 Oct;224:430-4; Sharifi M et al. Metab. Clin. Exp., 2016 Mar;65:48-53). 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.
PreventionGenetics, part of Exact Sciences	RCV003417769	SCV004118555	pathogenic	LDLR-related condition	2022-11-15	criteria provided, single submitter	clinical testing	The LDLR c.1705+1G>A variant is predicted to disrupt the GT donor site and interfere with normal splicing. This variant has been reported as pathogenic for autosomal dominant familial hypercholesterolemia (Jensen et al 1999. PubMed ID: 10532689; Table S1, Leren et al 2021. PubMed ID: 33740630; eTable 1, Sturm et al 2021. PubMed ID: 34037665; Chmara et al 2010. PubMed ID: 20145306; Sharifi et al 2015. PubMed ID: 26892515). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Variants that disrupt the consensus splice donor site in LDLR are expected to be pathogenic. This variant is interpreted as pathogenic.
Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital	RCV000211580	SCV000268630	pathogenic	Hypercholesterolemia, familial, 1	2011-06-01	no assertion criteria provided	clinical testing