Submissions for variant NM_000527.5(LDLR):c.1358+1G>A

dbSNP: rs775924858

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
LDLR-LOVD, British Heart Foundation	RCV000237640	SCV000295382	likely pathogenic	Hypercholesterolemia, familial, 1	2016-03-25	criteria provided, single submitter	literature only
Robarts Research Institute, Western University	RCV000237640	SCV000484786	likely pathogenic	Hypercholesterolemia, familial, 1		criteria provided, single submitter	clinical testing
Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix	RCV000237640	SCV000503339	pathogenic	Hypercholesterolemia, familial, 1	2016-12-16	criteria provided, single submitter	clinical testing	subject mutated among 2600 FH index cases screened = 1
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille	RCV000237640	SCV000583824	pathogenic	Hypercholesterolemia, familial, 1	2017-03-30	criteria provided, single submitter	clinical testing
Fundacion Hipercolesterolemia Familiar	RCV000237640	SCV000607590	pathogenic	Hypercholesterolemia, familial, 1	2016-03-01	criteria provided, single submitter	research
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV002479949	SCV002774353	pathogenic	not provided	2021-08-02	criteria provided, single submitter	clinical testing	This variant is located in a canonical splice-donor site and interferes with normal LDLR mRNA splicing. The variant has been reported in individuals affected with Familial Hypercholesteremia (FH) in the published literature (PMID: 24632281 (2014), 22390909 (2012), 19208450 (2009), 16627557 (2006), 15701167 (2005), 15241806 (2004)). Therefore, the variant is classified as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003581623	SCV004298356	pathogenic	Familial hypercholesterolemia	2023-05-19	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 9 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 present in population databases (rs775924858, gnomAD 0.0009%). Disruption of this splice site has been observed in individuals with familial hypercholesterolemia (PMID: 8314561, 15701167, 18096825). This variant is also known as IVS9+1G>A. ClinVar contains an entry for this variant (Variation ID: 251802). 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.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV004017556	SCV004847714	pathogenic	Homozygous familial hypercholesterolemia	2019-04-22	criteria provided, single submitter	clinical testing	The c.1358+1G>A variant in LDLR has been reported in at least 10 individuals with familial hypercholesterolemia (FH) and segregated with disease in 1 affected relative from 1 family (Top 1993, Mozas 2004, Zakharova 2005, ClinVar submission accessions: SCV000484786.1, SCV000503339.1, SCV000583824.1). It was absent from large population studies. This variant occurs within the canonical splice site (+/- 1,2) and is predicted to cause altered splicing leading to an abnormal or absent protein. Loss of function of the LDLR gene is an established disease mechanism in autosomal dominant FH. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant FH. ACMG/AMP Criteria applied: PVS1, PM2, PS4_Moderate.
All of Us Research Program, National Institutes of Health	RCV000237640	SCV005427598	pathogenic	Hypercholesterolemia, familial, 1	2024-08-19	criteria provided, single submitter	clinical testing	The c.1358+1G>A splice site variant in LDLR gene, that encodes for low density lipoprotein receptor, is located in intron 9. Computational prediction tools predict that this canonical splice site variant leads to donor loss which may disturb normal splicing, resulting in aberrant or absent protein product (SpliceAI: Donor loss: 1.00, Donor gain: 0.60 [+35bp]). This variant has been identified in multiple unrelated individuals (>10) affected with Familial Hypercholesterolemia (FH) (PMID:24632281, 22390909, 19208450, 16627557, 15701167, 15241806, 18096825). Experimental studies using patient-derived lymbhocytes revealed reduced LDLR transcript expression and possible nonsense-mediated mRNA decay (PMID: 19208450). Loss-of-function variants in LDLR are well known to be pathogenic and ClinGen score shows sufficient evidence of haploinsufficiency of this gene (PMID: 33740630, 15321837, 20809525, 28645073). Truncating variants downstream of this variant are reported to be pathogenic in the literature (PMID: 9254862, 10735632, 11668640) and by several ClinVar submitters (ClinVar ID: 251811, 251814). Other variants affecting this splice site, c.1358+1G>C, c.1358+1G>T, c.1358+2T>C, c.1358+2T>A have also been reported as pathogenic/likely pathogenic in ClinVar. This variant is absent in the general population database, gnomAD v2.1.1 and interpreted as likely pathogenic/pathogenic by multiple submitters in ClinVar (ID: 251802). Therefore, the c.1358+1G>A variant in the LDLR gene is classified as pathogenic.
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	RCV000237640	SCV000606404	pathogenic	Hypercholesterolemia, familial, 1		no assertion criteria provided	research