Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| LDLR- |
RCV000237358 | SCV000294501 | likely pathogenic | Hypercholesterolemia, familial, 1 | 2016-03-25 | criteria provided, single submitter | literature only | |
| Ambry Genetics | RCV004020946 | SCV005035883 | pathogenic | Cardiovascular phenotype | 2024-01-31 | criteria provided, single submitter | clinical testing | The c.190+1G>T intronic pathogenic mutation results from a G to T substitution one nucleotide after coding exon 2 of the LDLR gene. This alteration has been detected in a familial hypercholesterolemia cohort (Widhalm K et al. J Inherit Metab Dis, 2007 Apr;30:239-47). Other alterations impacting the same donor site (c.190+4A>T, and c.190+1G>A) have been described in numerous familial hypercholesterolemia cohorts (Peeters AV et al. Mol. Cell. Probes, 1999 Aug;13:257-60; Leren TP et al. Semin Vasc Med. 2004;4(1):75-85; Punzalan FE et al. J Atheroscler Thromb. 2005;12(5):276-83; Chmara M et al. J. Appl. Genet., 2010;51:95-106;Khateeb A et al. BMC Med Genet. 2011;12:40; Hooper AJ et al. Atherosclerosis. 2012;224(2):430-4; Vandrovcova J et al. Genet Med. 2013;15(12):948-57; Rutkowska L et al. Genes (Basel), 2022 Jun;13). The c.190+1G>T 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 donor site. 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 classified as a disease-causing mutation. |