Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| LDLR- |
RCV000238322 | SCV000295514 | likely pathogenic | Hypercholesterolemia, familial, 1 | 2016-03-25 | criteria provided, single submitter | literature only | |
| Ambry Genetics | RCV004020968 | SCV005035978 | pathogenic | Cardiovascular phenotype | 2024-02-01 | criteria provided, single submitter | clinical testing | The c.1587-2A>G intronic pathogenic mutation results from an A to G substitution two nucleotides upstream from coding exon 11 in the LDLR gene. This variant has been reported in a familial hypercholesterolemia cohort (Lind S et al. Atherosclerosis, 2002 Aug;163:399-407). Other alterations impacting the same donor site (c.1587-1G>A, c.1587-2A>T) have been described in subjects with familial hypercholesterolemia (Yu W et al. Atherosclerosis, 2002 Dec;165:335-42; Marduel M et al. Hum Mutat, 2010 Nov;31:E1811-24; Martin R et al. Atherosclerosis, 2016 Nov;254:8-13; Setia N et al. J Clin Lipidol, 2020 Jan;14:35-45). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site and will result in the creation or strengthening of a novel splice acceptor site. In addition to the clinical data 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. |