Total submissions: 11
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
LDLR- |
RCV000211683 | SCV000295055 | likely pathogenic | Familial hypercholesterolemia 1 | 2016-03-25 | criteria provided, single submitter | literature only | |
Robarts Research Institute, |
RCV000211683 | SCV000484690 | likely pathogenic | Familial hypercholesterolemia 1 | criteria provided, single submitter | clinical testing | ||
Centre de Génétique Moléculaire et Chromosomique, |
RCV000211683 | SCV000503253 | likely pathogenic | Familial hypercholesterolemia 1 | 2016-12-16 | criteria provided, single submitter | clinical testing | subject mutated among 2600 FH index cases screened = 1 , family member = 1 with co-segregation / FH-Amsterdam, 2 to 5% LDLR Activity / Software predictions: Conflicting |
Fundacion Hipercolesterolemia Familiar | RCV000211683 | SCV000607523 | likely pathogenic | Familial hypercholesterolemia 1 | 2016-03-01 | criteria provided, single submitter | research | |
Color | RCV001179372 | SCV001344023 | likely pathogenic | Familial hypercholesterolemia | 2019-12-29 | criteria provided, single submitter | clinical testing | |
Invitae | RCV001179372 | SCV001399727 | pathogenic | Familial hypercholesterolemia | 2019-08-20 | criteria provided, single submitter | clinical testing | This sequence change replaces serine with leucine at codon 306 of the LDLR protein (p.Ser306Leu). The serine residue is highly conserved and there is a large physicochemical difference between serine and leucine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in several individuals with familial hypercholesterolemia (FH) and segregates with FH in families (PMID: 21642693, 16542394, 30795984, 11462246, 7489239, 1301956, 22390909, 21475731, 10532689, 15199436). This variant is also known as S285L and FH-Amsterdam in the literature. ClinVar contains an entry for this variant (Variation ID: 226337). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). For these reasons, this variant has been classified as Pathogenic. |
Brunham Lab, |
RCV000211683 | SCV001432672 | pathogenic | Familial hypercholesterolemia 1 | 2019-06-05 | criteria provided, single submitter | research | |
Cardiovascular Genetics Laboratory, |
RCV000211683 | SCV000268589 | pathogenic | Familial hypercholesterolemia 1 | 2014-11-13 | no assertion criteria provided | clinical testing | |
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, |
RCV000211683 | SCV000606268 | pathogenic | Familial hypercholesterolemia 1 | no assertion criteria provided | research | ||
Diagnostic Laboratory, |
RCV000211683 | SCV000733816 | pathogenic | Familial hypercholesterolemia 1 | no assertion criteria provided | clinical testing | ||
Stanford Center for Inherited Cardiovascular Disease, |
RCV000786353 | SCV000925139 | pathogenic | not provided | 2016-09-06 | no assertion criteria provided | provider interpretation | The patient had genetic testing for the familial hypercholesterolemia panel. The test included sequencing of three genes associated with familial hypercholesterolemia: LDLR, APOB and PCSK9. Results showed that the following variant was identified (see report below): p.Ser306Leu (c.917C>T) in the LDLR gene (NM_000527.4) The lab classifies this variant as a pathogenic mutation. Given sufficient case data we consider this variant pathogenic and we do feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). The variant has been reported in at least 10 unrelated cases of familial hypercholesterolemia (not including this patient's family). There is strong case data. This variant has been identified in many individuals with familial hypercholesterolemia and one of the most prevalent variants in the Netherlands and has been known as the FH Amsterdam allele in publication (aka p.Ser285Leu). Hobbs, et al 1992 reported this variant in their cohort of Dutch patients. The individual had homozygous FH phenotype but the other variant could no be identified at the time of the study. Schuster, et al 1996 reports a family in which five individuals had the Ser306Leu variant in a heterozygous state and one individual who had p.Ser306Leu in a homozygous state. They had phenotypes of heterozygous and homozygous FH respectively. This study reported on a German cohort. Jensen, et al reported this variant in their Danish cohort in 1999. No individual details were provided other than the patient having the clinical diagnosis of FH. The Rotterdam study (Oosterveer, et al, 2015) identified Ser306Leu in 19 individuals (many unrelated individuals, but clinical information is not proved). Clinvar reports this variant in one individual that was tested at the PathWest Lab Medicine, no additional details are given. In silico analysis with PolyPhen-2 predicts the variant to be probably damaging (HumVar: 0.965). The serine at codon 306 is conserved across species, as are neighboring amino acids. There is no variation at codon 306 listed in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/), which currently includes variant calls on ~64,000 individuals of European, African, Latino and Asian descent (as of September 9, 2016). The average coverage at that site in ExAC is 80x. |