Total submissions: 13
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
LDLR- |
RCV000211575 | SCV000295306 | likely pathogenic | Familial hypercholesterolemia 1 | 2016-03-25 | criteria provided, single submitter | literature only | |
Cardiovascular Research Group, |
RCV000211575 | SCV000322937 | likely pathogenic | Familial hypercholesterolemia 1 | 2016-03-01 | criteria provided, single submitter | research | 0/208 non-FH alleles; 0/100 healthy control individuals |
Centre de Génétique Moléculaire et Chromosomique, |
RCV000211575 | SCV000503317 | likely pathogenic | Familial hypercholesterolemia 1 | 2016-12-16 | criteria provided, single submitter | clinical testing | subjects mutated among 2600 FH index cases screened = 11 , family members = 7 with co-segregation / previously described in association with FH/Software predictions: Benign |
U4M - |
RCV000211575 | SCV000583806 | pathogenic | Familial hypercholesterolemia 1 | 2017-03-30 | criteria provided, single submitter | clinical testing | |
Laboratory of Genetics and Molecular Cardiology, |
RCV000211575 | SCV000588566 | likely pathogenic | Familial hypercholesterolemia 1 | 2016-03-01 | criteria provided, single submitter | research | |
Fundacion Hipercolesterolemia Familiar | RCV000211575 | SCV000607575 | likely pathogenic | Familial hypercholesterolemia 1 | 2016-03-01 | criteria provided, single submitter | research | |
Iberoamerican FH Network | RCV000211575 | SCV000748143 | likely pathogenic | Familial hypercholesterolemia 1 | 2016-03-01 | criteria provided, single submitter | research | |
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, |
RCV000211575 | SCV000987565 | pathogenic | Familial hypercholesterolemia 1 | criteria provided, single submitter | clinical testing | ||
Invitae | RCV001045722 | SCV001209593 | pathogenic | Familial hypercholesterolemia | 2019-09-01 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine with tryptophan at codon 406 of the LDLR protein (p.Arg406Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs121908043, ExAC 0.01%). This variant has been observed in several individuals affected with familial hypercholesterolemia (PMID: 8882879, 25461735, 26343872, 25741862, 20538126, Invitae). This variant is also known as R385W in the literature. ClinVar contains an entry for this variant (Variation ID: 226351). This variant has been reported to affect LDLR protein function (PMID: 25741862). This variant disrupts the p.Arg406 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been observed in individuals with LDLR-related conditions (PMID: 16250003), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. |
Brunham Lab, |
RCV000211575 | SCV001432550 | pathogenic | Familial hypercholesterolemia 1 | 2018-12-07 | criteria provided, single submitter | research | |
Cardiovascular Genetics Laboratory, |
RCV000211575 | SCV000268604 | pathogenic | Familial hypercholesterolemia 1 | 2012-07-04 | no assertion criteria provided | clinical testing | |
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, |
RCV000211575 | SCV000606362 | pathogenic | Familial hypercholesterolemia 1 | no assertion criteria provided | research | ||
Broad Institute Rare Disease Group, |
RCV000211575 | SCV001422933 | pathogenic | Familial hypercholesterolemia 1 | 2020-01-22 | no assertion criteria provided | curation | The p.Arg406Trp variant in LDLR has been reported in at least 51 individuals (including 48 Portuguese, 1 Taiwanese, 1 Korean, and 1 Ashkenazi Jewish individuals) with Familial Hypercholesterolemia, segregated with disease in 48 affected relatives from 18 families (PMID: 17765246, 20538126, 26343872, 8882879, 25741862), and has been identified in 0.009658% (1/10354) of Ashkenazi Jewish chromosomes and 0.008021% (2/24936) of African chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs121908043). Please note that for diseases with clinical variability, or reduced penetrance, pathogenic variants may be present at a low frequency in the general population. This variant has also been reported likely pathogenic and pathogenic in ClinVar (Variation ID: 226351). In vitro functional studies provide some evidence that the p.Arg406Trp variant may impact cell surface expression and receptor activity (PMID: 25741862). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, this variant meets criteria to be classified as pathogenic for Familial Hypercholesterolemia in an autosomal dominant manner based on cosegregation with disease and multiple reports in individuals with Familial Hypercholesterolemia. ACMG/AMP Criteria applied: PP1_Strong, PS4, PS3_supporting, PP3 (Richards 2015). |