Submissions for variant NM_000527.5(LDLR):c.1586+5G>C

dbSNP: rs781362878

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000586202	SCV000627020	pathogenic	Familial hypercholesterolemia	2024-09-21	criteria provided, single submitter	clinical testing	This sequence change falls in intron 10 of the LDLR gene. It does not directly change the encoded amino acid sequence of the LDLR protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (no rsID available, gnomAD 0.02%). This variant has been observed in individuals with hypercholesterolemia (PMID: 12124988, 17964958, 23680767, 31345425; internal data). ClinVar contains an entry for this variant (Variation ID: 440652). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant disrupts the c.1586+5G nucleotide in the LDLR gene. Other variant(s) that disrupt this nucleotide have been determined to be pathogenic (PMID: 7635461, 10668928, 19208450). This suggests that this nucleotide is clinically significant, and that variants that disrupt this position are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000586202	SCV000697203	likely pathogenic	Familial hypercholesterolemia	2016-04-06	criteria provided, single submitter	clinical testing	Variant summary: c.1586+5G>C affects a conserved nucleotide, resulting in an intronic change. Mutation taster predicts this variant to be disease-causing. 5/5 programs in Alamut predict a loss (or weakening effect) of the canonical splicing donor site and ESE finder predicts changes of binding motifs for RNA splicing enhancers. This variant was not found in 117702 control chromosomes. This variant has been reported in multiple FH pts with evidence of segregation (Yang_JFormosMedAssoc_2008a). Taken together, this variant was classified as Likely Pathogenic until more information becomes available.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000586202	SCV001422708	uncertain significance	Familial hypercholesterolemia	2020-01-22	criteria provided, single submitter	curation	The c.1586+5G>C variant in LDLR has been reported in at least 2 Taiwanese individuals with familial hypercholesterolemia (PMID: 17964958), and has been identified in 0.02% (4/18384) of East Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs781362878). Please note that for diseases with clinical variability, or reduced penetrance, pathogenic variants may be present at a low frequency in the general population. This variant has also been reported in ClinVar as likely pathogenic and pathogenic (Variation ID#: 440652). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. This variant is located in the 5' splice region. Computational tools do suggest an impact to splicing. However, this information is not predictive enough to determine/rule out pathogenicity. In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PM2, PP3, PS4 (Richards 2015).
Brunham Lab, Centre for Heart and Lung Innovation, University of British Columbia	RCV000508837	SCV001432659	uncertain significance	Hypercholesterolemia, familial, 1	2019-03-10	criteria provided, single submitter	research
Mayo Clinic Laboratories, Mayo Clinic	RCV001509011	SCV001715492	likely pathogenic	not provided	2019-06-01	criteria provided, single submitter	clinical testing	PM1, PS4_moderate, PP1, PP3
GeneDx	RCV001509011	SCV002765327	uncertain significance	not provided	2022-06-16	criteria provided, single submitter	clinical testing	In-silico analysis is inconclusive as to whether the variant alters gene splicing, and in the absence of RNA/functional studies, the actual effect of this sequence change is unknown; This variant is associated with the following publications: (PMID: 34037665, 17964958, 23680767, 28964736, 31345425)
Ambry Genetics	RCV004023446	SCV003984201	uncertain significance	Cardiovascular phenotype	2024-06-18	criteria provided, single submitter	clinical testing	The c.1586+5G>C intronic variant results from a G to C substitution 5 nucleotides after coding exon 10 in the LDLR gene. This variant has been reported in familial hypercholesterolemia (FH) cohorts (Yang KC et al. J Formos Med Assoc, 2007 Oct;106:799-807; Vandrovcova J et al. Genet Med, 2013 Dec;15:948-57; Sturm AC et al. JAMA Cardiol, 2021 Aug;6:902-909). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration may weaken the native splice donor site. Based on the available evidence, the clinical significance of this variant remains unclear.
All of Us Research Program, National Institutes of Health	RCV000508837	SCV004828022	likely pathogenic	Hypercholesterolemia, familial, 1	2023-08-28	criteria provided, single submitter	clinical testing	This variant causes a G to C nucleotide substitution at the +5 position of intron 10 of the LDLR gene. Although functional RNA studies have not been reported for this variant, it is predicted to impair RNA splicing and affect gene function. This variant has been reported in several individuals affected with familial hypercholesterolemia (PMID: 17964958, 23680767, 28964736, 31345425; ClinVar SCV000627020.3) and claimed to segregate with disease in affected families (PMID: 17964958). This variant has been identified in 4/250846 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different variant occurring at the same position, c.1586+5G>A, is known to be pathogenic (ClinVar variation ID: 251909), indicating that c.G nucleotide at this position is important for normal RNA splicing. Based on the available evidence, this variant is classified as Likely Pathogenic.
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	RCV000508837	SCV000606462	pathogenic	Hypercholesterolemia, familial, 1		no assertion criteria provided	research
Natera, Inc.	RCV000586202	SCV001460279	likely pathogenic	Familial hypercholesterolemia	2020-09-16	no assertion criteria provided	clinical testing
Amrita Institute of Medical Sciences and Research Centre, Amrita Vishwa Vidyapeetham	RCV000586202	SCV005205793	uncertain significance	Familial hypercholesterolemia	2023-01-01	no assertion criteria provided	clinical testing	c.1586+5G>C affects a conserved nucleotide, resulting in an intronic change. Mutation taster predicts this variant to be disease-causing. This variant has been reported in multiple FH pts with evidence of segregation (Yang_JFormosMedAssoc_2008a)