Total submissions: 9
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
LDLR- |
RCV000211687 | SCV000294607 | likely pathogenic | Hypercholesterolemia, familial, 1 | 2016-03-25 | criteria provided, single submitter | literature only | |
Centre de Génétique Moléculaire et Chromosomique, |
RCV000211687 | SCV000503135 | likely pathogenic | Hypercholesterolemia, familial, 1 | 2016-12-16 | criteria provided, single submitter | clinical testing | subject mutated among 2600 FH index cases screened = 1, family member=1 |
U4M - |
RCV000211687 | SCV000583656 | pathogenic | Hypercholesterolemia, familial, 1 | 2017-03-30 | criteria provided, single submitter | clinical testing | |
Fundacion Hipercolesterolemia Familiar | RCV000211687 | SCV000607442 | likely pathogenic | Hypercholesterolemia, familial, 1 | 2016-03-01 | criteria provided, single submitter | research | |
Iberoamerican FH Network | RCV000211687 | SCV000748083 | likely pathogenic | Hypercholesterolemia, familial, 1 | 2016-03-01 | criteria provided, single submitter | research | |
Invitae | RCV001054512 | SCV001218830 | pathogenic | Familial hypercholesterolemia | 2024-01-24 | criteria provided, single submitter | clinical testing | This sequence change falls in intron 3 of the LDLR gene. It does not directly change the encoded amino acid sequence of the LDLR protein. RNA analysis indicates that this variant induces altered splicing and likely results in a shortened protein product. This variant is present in population databases (no rsID available, gnomAD 0.006%). This variant has been observed in individuals with familial hypercholesterolemia (PMID: 15241806, 21990180). ClinVar contains an entry for this variant (Variation ID: 226317). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of exon 3, but is expected to preserve the integrity of the reading-frame (PMID: 21990180). For these reasons, this variant has been classified as Pathogenic. |
Ambry Genetics | RCV002321828 | SCV002607539 | pathogenic | Cardiovascular phenotype | 2018-12-21 | criteria provided, single submitter | clinical testing | The c.313+2dupT intronic pathogenic mutation, results from a duplication of a T nucleotide two nucleotide positions after coding exon 3 of the LDLR gene. This alteration has been detected as homozgyous in multiple individuals with clinically confirmed homozygous familial hypercholesterolemia (HoFH) (Sánchez-Hernández RM et al. Circ Cardiovasc Genet, 2016 Dec;9:504-510; Alonso R et al. J Clin Lipidol Apr;10:953-961) and as heterozygous in multiple individuals with familial hypercholesterolemia (FH) (Bañares VG et al. J Clin Lipidol Feb;11:524-531; Gabová D et al. Physiol Res, 2017 Mar;66:75-84; Mozas P et al. Hum. Mutat., 2004 Aug;24:187). In one functional study, authors showed that this mutation impacts ligand binding and results in the skipping of in-frame exon 3 at the mRNA level (Etxebarria A et al. Hum. Mutat., 2012 Jan;33:232-43). In addition, a different alteration with the same molecular splicing impact, c.313+6T>C, has been detected in individuals with FH and has been shown at the mRNA level to induce exon 3 skipping (Bourbon M et al. Atherosclerosis, 2008 Feb;196:633-42). (Bourbon M et al. J. Med. Genet., 2009 May;46:352-7). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. |
Cardiovascular Genetics Laboratory, |
RCV000211687 | SCV000268555 | pathogenic | Hypercholesterolemia, familial, 1 | 2013-07-04 | no assertion criteria provided | clinical testing | |
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, |
RCV000211687 | SCV000606076 | pathogenic | Hypercholesterolemia, familial, 1 | no assertion criteria provided | research |