Submissions for variant NM_000527.5(LDLR):c.1056_1060+3del

dbSNP: rs879254770

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
LDLR-LOVD, British Heart Foundation	RCV000237871	SCV000295169	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	RCV000237871	SCV000503288	pathogenic	Hypercholesterolemia, familial, 1	2016-12-16	criteria provided, single submitter	clinical testing	subjects mutated among 2600 FH index cases screened = 4 , family member =1
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille	RCV000237871	SCV000583781	pathogenic	Hypercholesterolemia, familial, 1	2017-03-30	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000589532	SCV000697182	pathogenic	Familial hypercholesterolemia	2023-03-21	criteria provided, single submitter	clinical testing	Variant summary: Several computational tools predict a significant impact on normal splicing: Three predict the variant abolishes a 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 250660 control chromosomes. c.1056_1060+3delCGAAGGTG has been reported in the literature in individuals affected with Familial Hypercholesterolemia and in an individual with early onset myocardial infarction (Humphries_2006, Khera_2019, Abul-Husn_2016). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000844740	SCV000731750	pathogenic	Homozygous familial hypercholesterolemia	2017-10-16	criteria provided, single submitter	clinical testing	The c.1056_1060+3del variant in LDLR has been reported in 1 individual with fami lial hypercholesterolemia (FH; Humphries 2006) and in several individuals with F H in ClinVar (Variation ID# 251620). This variant has also been identified in 1/ 8722 African chromosomes by the Genome Aggregation Database (GnomAD, http://gnom ad.broadinstitute.org; dbSNP rs879254770). This frequency is low enough to be co nsistent with the frequency of FH in the general population. This deletion spans the (+/- 1,2) invariant region of the 5' splice consensus sequence and is predi cted to cause altered splicing leading to an abnormal or absent protein. Heteroz ygous loss of function of the LDLR gene is an established disease mechanism in F H. In summary, this variant meets criteria to be classified as pathogenic for FH in an autosomal dominant manner based upon the predicted impact to the protein, presence in multiple affected individuals and very low frequency in the general population.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000589532	SCV000830563	pathogenic	Familial hypercholesterolemia	2025-01-19	criteria provided, single submitter	clinical testing	This variant results in the deletion of exon 7 (c.1056_1060+3del) 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 (no rsID available, gnomAD 0.01%). This variant has been observed in individuals with clinical features of familial hypercholesterolemia (PMID: 16389549, 28008010, 30586733; internal data). Invitae Evidence Modeling of clinical and family history, age, sex, and reported ancestry of multiple individuals with this LDLR variant has been performed. This variant is expected to be pathogenic with a positive predictive value of at least 99%. This is a validated machine learning model that incorporates the clinical features of 363,995 individuals referred to our laboratory for LDLR testing. This variant is also known as p.C331fs and p.Cys352fs. ClinVar contains an entry for this variant (Variation ID: 251620). For these reasons, this variant has been classified as Pathogenic.
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	RCV000237871	SCV000839979	pathogenic	Hypercholesterolemia, familial, 1	2017-06-05	criteria provided, single submitter	clinical testing	This c.1056_1060+3del (p.Cys352*) variant has not been observed in our cohort database nor has been detected in the ExAC population database. This variant deletes 8 nucleotides from cDNA postion c.1056 to c.1060+3, which includes the donor splice site of intron 7 of the LDLR gene. Computer algorithm predict the use of an alternative splice site at position c.1060+12_1060+13 and the creation of a non sense variant and a stop codon at amino acid position 352 of the LDLR protein. This variant is thus classified as pathogenic.
GeneDx	RCV001820791	SCV002064181	likely pathogenic	not provided	2024-09-20	criteria provided, single submitter	clinical testing	Identified in a patient with early onset myocardial infarction in published literature (PMID: 30586733); Not observed at significant frequency in large population cohorts (gnomAD); Deletions involving coding exons of this gene are a known mechanism of disease (HGMD); Canonical splice site variant predicted to result in an in-frame loss of the adjacent exon in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 31447099, 28008010, 34037665, 32220565, 34363016, 16389549, 37589137, 30586733)
AiLife Diagnostics, AiLife Diagnostics	RCV001820791	SCV002502292	pathogenic	not provided	2022-02-11	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002401932	SCV002710499	pathogenic	Cardiovascular phenotype	2023-03-21	criteria provided, single submitter	clinical testing	The c.1056_1060+3delCGAAGGTG pathogenic mutation results from a deletion of 8 nucleotides between positions 1056 and 1060+3 and involves the canonical splice donor site after coding exon 7 of the LDLR gene. This alteration has been reported in a familial hypercholesterolemia cohort (Humphries SE et al. J. Mol. Med., 2006 Mar;84:203-14). 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 interpreted as a disease-causing mutation.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001820791	SCV004219934	pathogenic	not provided	2023-04-13	criteria provided, single submitter	clinical testing	The LDLR c.1056_1060+3del variant disrupts a canonical splice-donor site and interferes with normal LDLR mRNA splicing. It is also predicted to create a premature stop codon (p.Cys352*) that may disrupt normal LDLR protein synthesis. The frequency of this variant in the general population, 0.000032 (1/31382 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. In the published literature, the variant has been reported in multiple individuals with clinical features of familial hypercholesterolemia (PMIDs: 34363016 (2021), 34037665 (2021), 32220565 (2020), 30586733 (2019), 28008010 (2016), 16389549 (2006)). Based on the available information, this variant is classified as pathogenic.
All of Us Research Program, National Institutes of Health	RCV000237871	SCV004822564	pathogenic	Hypercholesterolemia, familial, 1	2023-12-18	criteria provided, single submitter	clinical testing	This variant deletes eight nucleotides spanning the boundary of exon 7 and intron 7 of the LDLR gene, deleting the canonical splice donor site, and creating a premature translation stop signal at the deletion boundary. Use of a downstream cryptic donor would allow use of this stop codon and would result in a protein truncation (p.Cys352*). However in-frame skipping of exon 7 may also occur. To our knowledge RNA studies on this variant have not been reported. This variant has been reported in individuals affected with familial hypercholesterolemia (PMID: 16389549, 28008010, 32220565, 34037665). This variant has also been observed in compound heterozygous state with a known pathogenic LDLR variant in an individual affected with severe homozygous familial hypercholesterolemia, a phenotype expected of having two deleterious LDLR variants (PMID: 34029164). This variant has been identified in 1/31382 chromosomes 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.