Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| LDLR- |
RCV000237720 | SCV000294997 | likely pathogenic | Hypercholesterolemia, familial, 1 | 2016-03-25 | criteria provided, single submitter | literature only | |
| U4M - |
RCV000237720 | SCV000583744 | pathogenic | Hypercholesterolemia, familial, 1 | 2017-03-30 | criteria provided, single submitter | clinical testing | |
| Invitae | RCV001206766 | SCV001378090 | pathogenic | Familial hypercholesterolemia | 2022-09-28 | criteria provided, single submitter | clinical testing | This variant is also known as IVS5-1G>A. 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: 251475). Disruption of this splice site has been observed in individuals with familial hypercholesterolemia (PMID: 16389549, 17765246, 17935672, 33740630). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change affects an acceptor splice site in intron 5 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). |
| Ambry Genetics | RCV002429170 | SCV002681176 | pathogenic | Cardiovascular phenotype | 2022-09-06 | criteria provided, single submitter | clinical testing | The c.818-1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide upstream from coding exon 6 of the LDLR gene. This alteration has been detected in a familial hypercholesterolemia (FH) cohort (Humphries SE et al. J. Mol. Med., 2006 Mar;84:203-14). It was also reported in the homozygous state in a Chinese male with a homozygous FH phenotype, who was additionally heterozygous for the LDLR p.W165* pathogenic mutation (Xie L et al. Chin. Med. J., 2007 Oct;120:1694-9). A disease-causing mutation impacting the same canonical acceptor splice site, c.818-2A>G, has also been described (Bourbon M et al. Atherosclerosis, 2008 Feb;196:633-42). RNA studies for both c.818-1G>A and c.818-2A>G have been reported to cause retention of the same 10 intronic nucleotides between exons 5 and 6, resulting in a frameshift with a predicted alternate stop codon (Xie L et al. Chin. Med. J., 2007 Oct;120:1694-9; Medeiros AM et al. Atherosclerosis, 2010 Oct;212:553-8). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. |