Submissions for variant NM_000527.5(LDLR):c.817+1G>A

dbSNP: rs879254685

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
LDLR-LOVD, British Heart Foundation	RCV000237841	SCV000294991	likely pathogenic	Hypercholesterolemia, familial, 1	2016-03-25	criteria provided, single submitter	literature only
Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation	RCV000237841	SCV000540762	pathogenic	Hypercholesterolemia, familial, 1	2016-11-05	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001193787	SCV001362898	pathogenic	Familial hypercholesterolemia	2019-09-30	criteria provided, single submitter	clinical testing	Variant summary: LDLR c.817+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: Five predict the variant abolishes a 5' splicing donor site. These predictions are supported by a functional study, Vandrovcova_2013, that found the variant to affect splicing. The variant was absent in 251430 control chromosomes (gnomAD). c.817+1G>A has been reported in the literature in multiple individuals affected with Familial Hypercholesterolemia including a homozygous individual (Duskova_2011, Hu_2016, Vandrovcova_2013, Chiou_2017, Lin_2004). These data indicate that the variant is very likely to be associated with disease. Three ClinVar submissions (evaluation after 2014) cite the variant twice as pathogenic and once as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001193787	SCV001373984	pathogenic	Familial hypercholesterolemia	2023-05-01	criteria provided, single submitter	clinical testing	ClinVar contains an entry for this variant (Variation ID: 251469). Disruption of this splice site has been observed in individuals with familial hypercholesterolemia (PMID: 21310417, 23680767, 26875521). This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor splice site in intron 5 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). 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.
Fulgent Genetics, Fulgent Genetics	RCV000237841	SCV002792056	pathogenic	Hypercholesterolemia, familial, 1	2021-10-16	criteria provided, single submitter	clinical testing
Juno Genomics, Hangzhou Juno Genomics, Inc	RCV000237841	SCV005417562	pathogenic	Hypercholesterolemia, familial, 1		criteria provided, single submitter	clinical testing	PM2_Supporting+PVS1_Strong+PS4+PP4
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	RCV000237841	SCV000606234	pathogenic	Hypercholesterolemia, familial, 1		no assertion criteria provided	research