Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV002378150 | SCV002668268 | pathogenic | Cardiovascular phenotype | 2020-03-26 | criteria provided, single submitter | clinical testing | The c.695-1G>C intronic pathogenic mutation results from a G to C substitution one nucleotide upstream from coding exon 5 of the LDLR gene. A pathogenic alteration at the same nucleotide position (c.695-1G>T) has been reported in several patients with a clinical diagnosis of hypercholesterolemia (Vaca G et al. Atherosclerosis, 2011 Oct;218:391-6). In addition, 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 classified as a disease-causing mutation. |
| Labcorp Genetics |
RCV003098427 | SCV003196438 | pathogenic | Familial hypercholesterolemia | 2023-06-07 | criteria provided, single submitter | clinical testing | Disruption of this splice site has been observed in individuals with familial hypercholesterolemia (PMID: 21722902). 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: 1756297). This variant is not present in population databases (gnomAD no frequency). This sequence change affects an acceptor splice site in intron 4 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). |