Total submissions: 9
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
LDLR- |
RCV000238063 | SCV000295611 | likely pathogenic | Familial hypercholesterolemia 1 | 2016-03-25 | criteria provided, single submitter | literature only | |
Centre de Génétique Moléculaire et Chromosomique, |
RCV000238063 | SCV000503397 | uncertain significance | Familial hypercholesterolemia 1 | 2016-12-16 | criteria provided, single submitter | clinical testing | subject mutated among 2600 FH index cases screened = 1, family member=1 /FH-Germany/software prediction damaging |
Fundacion Hipercolesterolemia Familiar | RCV000238063 | SCV000607630 | uncertain significance | Familial hypercholesterolemia 1 | 2016-03-01 | criteria provided, single submitter | research | |
Invitae | RCV000791378 | SCV000752408 | pathogenic | Familial hypercholesterolemia | 2019-09-22 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine with cysteine at codon 574 of the LDLR protein (p.Arg574Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs185098634, ExAC 0.02%). This variant has been reported in several individuals affected with hypercholesterolemia (PMID: 11462246, 19446849, 26892515), probable hypercholesterolemia (PMID: 23375686, 20145306), and myocardial infarction (PMID: 25487149). ClinVar contains an entry for this variant (Variation ID: 183123). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Different missense substitutions at this codon (p.Arg574His, p.Arg574Ser, p.Arg574Leu) have been reported in several individuals affected with hypercholesterolemia (PMID: 28028493, 20018285, 22698793). This suggests that the arginine residue is critical for LDLR protein function. For these reasons, this variant has been classified as Pathogenic. |
Ce |
RCV000161998 | SCV001151665 | likely pathogenic | not provided | 2018-10-01 | criteria provided, single submitter | clinical testing | |
Color | RCV000791378 | SCV001349170 | likely pathogenic | Familial hypercholesterolemia | 2019-01-02 | criteria provided, single submitter | clinical testing | |
Dept. |
RCV000161998 | SCV000189573 | not provided | not provided | no assertion provided | in vitro | ||
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, |
RCV000238063 | SCV000606498 | pathogenic | Familial hypercholesterolemia 1 | no assertion criteria provided | research | ||
Broad Institute Rare Disease Group, |
RCV000238063 | SCV001423052 | uncertain significance | Familial hypercholesterolemia 1 | 2020-01-22 | no assertion criteria provided | curation | The p.Arg574Cys variant in LDLR has been reported in 14 individuals with familial hypercholesterolemia (PMID: 29290422, 25647241, 22698793, 20145306, 25487149, 23375686, 11462246, 26892515, 19446849), and has been identified in 0.006% (8/129194) European non-Finnish chromosomes. 0.004% (1/25116) European Finnish chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs185098634). 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 in ClinVar as a VUS, likely pathogenic, and pathogenic(Variation ID#: 183123). 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, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PS4_moderate, PM2_supporting, PP3 (Richards 2015). |