Submissions for variant NM_000527.5(LDLR):c.1187-2A>G

dbSNP: rs879254823

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
LDLR-LOVD, British Heart Foundation	RCV000237447	SCV000295274	likely pathogenic	Hypercholesterolemia, familial, 1	2016-03-25	criteria provided, single submitter	literature only
GeneDx	RCV000482482	SCV000568522	pathogenic	not provided	2017-03-13	criteria provided, single submitter	clinical testing	The c.1187-2 A>G variant has been reported in the heterozygous state in one Norwegian proband with FH (Holla et al., 2009). This variant destroys the canonical splice acceptor site located at the intron 8/exon 9 junction, and is predicted to cause abnormal gene splicing. This variant is predicted to lead to an abnormal message that is subject to nonsense-mediated mRNA decay, consistent with comprehensive mRNA splicing studies determined by wet-lab analyses in the same study by Holla et al. (2009). In addition, other downstream splice site variants in the LDLR gene have been reported in HGMD in association with FH (Stenson et al., 2014), indicating that loss of function is a known disease mechanism. Furthermore, the c.1187-2 A>G variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). In summary, c.1187-2 A>G in the LDLR gene is interpreted as a pathogenic variant.
Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge	RCV000237447	SCV000599366	pathogenic	Hypercholesterolemia, familial, 1	2016-03-01	criteria provided, single submitter	curation
Invitae	RCV002518485	SCV003443874	pathogenic	Familial hypercholesterolemia	2022-05-12	criteria provided, single submitter	clinical testing	Studies have shown that disruption of this splice site alters LDLR gene expression (PMID: 19208450). This sequence change affects an acceptor splice site in intron 8 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). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with familial hypercholesterolemia (PMID: 19208450). ClinVar contains an entry for this variant (Variation ID: 251713). 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.
Revvity Omics, Revvity	RCV000237447	SCV004237269	pathogenic	Hypercholesterolemia, familial, 1	2023-06-14	criteria provided, single submitter	clinical testing
Clinical Genetics, Academic Medical Center	RCV000482482	SCV001924651	pathogenic	not provided		no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000482482	SCV001963545	pathogenic	not provided		no assertion criteria provided	clinical testing