Submissions for variant NM_000527.5(LDLR):c.941-2A>G

dbSNP: rs112366278

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
LDLR-LOVD, British Heart Foundation	RCV000237558	SCV000295091	likely pathogenic	Hypercholesterolemia, familial, 1	2016-03-25	criteria provided, single submitter	literature only
Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix	RCV000237558	SCV000503266	likely pathogenic	Hypercholesterolemia, familial, 1	2016-12-16	criteria provided, single submitter	clinical testing	subject mutated among 2600 FH index cases screened = 1 , family member = 1
Labcorp Genetics (formerly Invitae), Labcorp	RCV001034626	SCV000544681	pathogenic	Familial hypercholesterolemia	2023-08-08	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: 251554). This variant is also known as IVS6-2A>G. Disruption of this splice site has been observed in individuals with familial hypercholesterolemia (PMID: 12436241, 25962062). This variant is not present in population databases (gnomAD no frequency). This sequence change affects an acceptor splice site in intron 6 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).
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV003477851	SCV004220005	pathogenic	not provided	2024-02-20	criteria provided, single submitter	clinical testing	The LDLR c.941-2A>G variant disrupts a canonical splice-acceptor site and interferes with normal LDLR mRNA splicing. This variant has been reported in the published literature in individuals with hypercholesterolemia (PMIDs: 12436241 (2002), 25962062 (2015), 33418990 (2021), 34456200 (2021), 35910211 (2022)). Additionally, this variant resides in a region of the LDLR gene that is important for proper protein function (PMIDs: 22081141 (2011), 28587771 (2017)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Based on the available information, this variant is classified as pathogenic.
All of Us Research Program, National Institutes of Health	RCV000237558	SCV004827279	likely pathogenic	Hypercholesterolemia, familial, 1	2023-12-10	criteria provided, single submitter	clinical testing	The c.941-2A>G canonical splice site variant in LDLR gene has been identified in at least four individuals who fulfill the clinical criteria of Familial Hypercholesterolemia (FH) (PMID: 12436241, 25962062, 34456200, 33418990). In-silico computational prediction tools suggest that this variant likely leads to acceptor loss (SpliceAI: 0.9934) and disturbs normal splicing, resulting in an aberrant or absence of protein product (PMID: 16199547). Loss-of-function variants in LDLR are known to be pathogenic (PMID: 33740630, 15321837, 20809525, 28645073). Truncating variants downstream of this variant are reported to be pathogenic in the literature (PMID: 16389549, 28008010, 30586733). This variant is absent in the general population database (gnomAD) and interpreted as likely pathogenic/pathogenic by several submitters in the ClinVar database (ClinVar ID: 251554). Therefore, the c.941-2A>G variant in the LDLR gene is classified as likely pathogenic.
Neuberg Centre For Genomic Medicine, NCGM	RCV000237558	SCV005438974	pathogenic	Hypercholesterolemia, familial, 1	2023-07-22	criteria provided, single submitter	clinical testing	The observed splice acceptor variant c.941-2A>G in LDLR gene has been reported previously in individuals with familial hypercholesterolemia Han SM, et al., 2015, Amsellem S, et al., 2002. The c.941-2A>G variant is absent in gnomAD Exomes. It has been submitted to ClinVar as Likely Pathogenic/ Pathogenic. This variant is predicted to be Damging by SpliceAI Prediction. This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants have been previously reported to be disease causing Jiang L, et al., 2017. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV004992116	SCV005609306	pathogenic	Cardiovascular phenotype	2024-12-06	criteria provided, single submitter	clinical testing	The c.941-2A>G intronic pathogenic mutation results from an A to G substitution two nucleotides upstream from coding exon 7 in the LDLR gene. Alterations that disrupt the canonical splice site are expected to result in aberrant splicing. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site. A resulting transcript is predicted to be in-frame and is not expected to trigger nonsense-mediated mRNAdecay; although, direct evidence is unavailable. However, the region predicted to be impacted is critical for protein function (Ambry internal data). This variant (also referred to as IVS6-2A>G) was reported in individual(s) with features consistent with familial hypercholesterolemia (FH) (Amsellem S et al. Hum Genet, 2002 Dec;111:501-10; Han SM et al. PLoS One, 2015 May;10:e0126706; Meshkov A et al. Genes (Basel), 2021 Jan;12). Other variant(s) impacting the same acceptor site (c.941-2A>C) have been identified in individual(s) with features consistent with FH (Chmara M et al. J Appl Genet, 2010;51:95-106). This nucleotide position is highly conserved in available vertebrate species. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this variant is interpreted as a disease-causing mutation.
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	RCV000237558	SCV000606282	pathogenic	Hypercholesterolemia, familial, 1		no assertion criteria provided	research