Submissions for variant NM_000527.5(LDLR):c.1845+1G>A

dbSNP: rs879255049

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
LDLR-LOVD, British Heart Foundation	RCV000237195	SCV000295698	likely pathogenic	Hypercholesterolemia, familial, 1	2016-03-25	criteria provided, single submitter	literature only
Robarts Research Institute, Western University	RCV000237195	SCV000484789	likely pathogenic	Hypercholesterolemia, familial, 1		criteria provided, single submitter	clinical testing
Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation	RCV000237195	SCV000540841	pathogenic	Hypercholesterolemia, familial, 1	2016-11-05	criteria provided, single submitter	clinical testing
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille	RCV000237195	SCV000583891	pathogenic	Hypercholesterolemia, familial, 1	2017-03-30	criteria provided, single submitter	clinical testing
Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge	RCV000237195	SCV000599395	pathogenic	Hypercholesterolemia, familial, 1	2016-03-01	criteria provided, single submitter	curation
Invitae	RCV001857829	SCV002126040	pathogenic	Familial hypercholesterolemia	2021-12-02	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 252067). Disruption of this splice site has been observed in individuals with familial hypercholesterolemia (PMID: 15556094, 21115573). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). 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).
Ambry Genetics	RCV003165671	SCV003912556	pathogenic	Cardiovascular phenotype	2022-11-18	criteria provided, single submitter	clinical testing	The c.1845+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 12 of the LDLR gene. This alteration, also known as FH Tunis, has been reported as heterozygous and homozygous in subjects with familial hypercholesterolemia (FH) (Jelassi A et al. Ann Clin Biochem, 2011 Jan;48:83-6; Laurie AD et al. Atheroscler Suppl, 2004 Dec;5:13-5; Dušková L et al. Atherosclerosis, 2011 May;216:139-45; Wang J et al. Arterioscler Thromb Vasc Biol, 2016 12;36:2439-2445). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In silico splice site analysis predicts that this alteration will weaken the native splice donor site and may result in the creation or strengthening of a novel splice donor site. 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.
Color Diagnostics, LLC DBA Color Health	RCV001857829	SCV004359046	pathogenic	Familial hypercholesterolemia	2023-11-14	criteria provided, single submitter	clinical testing	This variant causes a G to A nucleotide substitution at the + 1 canonical donor position of intron 12 of the LDLR gene. Splice site prediction tools suggest that this variant may have a significant impact on RNA splicing. Although this prediction has not been confirmed in published RNA studies, this variant is expected to result in an absent or disrupted protein product. Functional studies using cultured fibroblasts derived from individuals homozygous for this variant and clinically affected with familial hypercholesterolemia have shown that this variant causes a significant reduction in LDL receptor activity (PMID: 1301956, 21115573). This LDLR variant has been reported in at least seven heterozygous individuals affected with familial hypercholesterolemia (PMID: 1301956, 15556094, 21115573, 21310417, 22417841, 27765764, 28645073). This variant has also been observed in compound heterozygous state with a known pathogenic LDLR variant in one individual affected with severe homozygous familial hypercholesterolemia, a phenotype expected of having two deleterious LDLR variants (PMID: 36325061). It has been shown that this variant segregates with disease in multiple affected individuals across two families (PMID: 21115573). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of LDLR function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	RCV000237195	SCV000606535	pathogenic	Hypercholesterolemia, familial, 1		no assertion criteria provided	research