Total submissions: 16
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
LDLR- |
RCV000237918 | SCV000294548 | likely pathogenic | Familial hypercholesterolemia 1 | 2016-03-25 | criteria provided, single submitter | literature only | |
Cardiovascular Research Group, |
RCV000237918 | SCV000322881 | uncertain significance | Familial hypercholesterolemia 1 | 2016-03-01 | criteria provided, single submitter | research | 0/208 non-FH alleles |
Centre de Génétique Moléculaire et Chromosomique, |
RCV000237918 | SCV000503115 | likely pathogenic | Familial hypercholesterolemia 1 | 2016-12-16 | criteria provided, single submitter | clinical testing | subjects mutated among 2600 FH index cases screened = 2 / Functional test / Software predictions: Damaging |
Invitae | RCV001186037 | SCV000544662 | likely pathogenic | Familial hypercholesterolemia | 2019-06-12 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine with cysteine at codon 81 of the LDLR protein (p.Arg81Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs730882078, ExAC 0.001%). This variant has been reported in several individuals and families affected with familial hypercholesterolemia (PMID: 9712531, 11810272, 17765246, 21642693, 23375686). This variant is also known as p.Arg60Cys in the literature. ClinVar contains an entry for this variant (Variation ID: 183083). 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 C0"). This variant disrupts the p.Arg81 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been observed in individuals with LDLR-related conditions (PMID: 21382890), which suggests that this may be a clinically significant amino acid residue. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. |
Laboratory of Genetics and Molecular Cardiology, |
RCV000237918 | SCV000588490 | uncertain significance | Familial hypercholesterolemia 1 | 2016-03-01 | criteria provided, single submitter | research | |
Fundacion Hipercolesterolemia Familiar | RCV000237918 | SCV000607434 | uncertain significance | Familial hypercholesterolemia 1 | 2016-03-01 | criteria provided, single submitter | research | |
Integrated Genetics/Laboratory Corporation of America | RCV000586143 | SCV000697229 | pathogenic | Early-onset coronary artery disease | 2016-09-06 | criteria provided, single submitter | clinical testing | Variant summary: The LDLR c.241C>T (p.Arg81Cys) variant involves the alteration of a conserved nucleotide and results in a replacement of a large size and basic Arginine (R) with a medium size and polar Cysteine (C) located in the ligand binding domain of LDLR. 5/5 in silico tools predict a damaging outcome for this substitution. This variant was found in 1/121500 control chromosomes at a frequency of 0.0000082, which does not exceed the estimated maximal expected allele frequency of a pathogenic LDLR variant (0.0010005). It was observed in several FH patients indicating pathogenicity. In addition, a clinical diagnostic laboratory classified this variant as likely pathogenic. Taken together, this variant is classified as pathogenic. |
Iberoamerican FH Network | RCV000237918 | SCV000748161 | uncertain significance | Familial hypercholesterolemia 1 | 2016-03-01 | criteria provided, single submitter | research | |
Laboratory for Molecular Medicine, |
RCV000826092 | SCV000967594 | likely pathogenic | Homozygous familial hypercholesterolemia | 2020-04-14 | criteria provided, single submitter | clinical testing | proposed classification - variant undergoing re-assessment, contact laboratory |
Biesecker Lab/Clinical Genomics Section, |
RCV000237918 | SCV001132526 | likely pathogenic | Familial hypercholesterolemia 1 | 2018-01-10 | criteria provided, single submitter | curation | |
Color Health, |
RCV001186037 | SCV001352367 | likely pathogenic | Familial hypercholesterolemia | 2019-12-16 | criteria provided, single submitter | clinical testing | |
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, |
RCV000161952 | SCV001433516 | likely pathogenic | not provided | 2019-12-16 | criteria provided, single submitter | clinical testing | |
Human Genome Sequencing Center Clinical Lab, |
RCV001186037 | SCV001434983 | likely pathogenic | Familial hypercholesterolemia | 2019-08-20 | criteria provided, single submitter | clinical testing | The c.241C>T (p.Arg81Cys) variant in the LDLR gene has been reported in multiple unrelated individuals and families with familial hypercholesterolemia (PMID: 9712531, 10422804, 11810272, 17765246, 19318025, 21642693, 23375686, 25487149) and is rare in population databases. Multiple lines of in silico algorithms have predicted this Arg81Cys change to be deleterious. Therefore, this c.241C>T (p.Arg81Cys) variant is classified as likely pathogenic. |
Dept. |
RCV000161952 | SCV000189527 | not provided | not provided | no assertion provided | in vitro | ||
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, |
RCV000237918 | SCV000606046 | pathogenic | Familial hypercholesterolemia 1 | no assertion criteria provided | research | ||
Broad Institute Rare Disease Group, |
RCV001186037 | SCV001422748 | uncertain significance | Familial hypercholesterolemia | 2020-01-22 | no assertion criteria provided | curation | The p.Arg81Cys variant in LDLR has been reported in at least 12 individuals (2 African, 1 Italian, 1 Malaysian, 1 Venezuelan, 6 Dutch, 1 Portuguese) with familial hypercholesterolemia (PMID: 11845603, 28161202, 29353225, 28895539, 10422804, 21642693, 9712531, 17765246, 11810272), and has been identified in 0.002% (2/113766) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs730882078). This variant has (also) been reported in ClinVar as having conflicting interpretations of pathogenicity (Variation ID: 183083). In vitro functional studies provide some evidence that the p.Arg81Cys variant may slightly impact protein function (PMID: 25647241). 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, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PS4_moderate, PP3, PS3_supporting (Richards 2015). |