Total submissions: 6
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Clin |
RCV000238365 | SCV004022401 | pathogenic | Hypercholesterolemia, familial, 1 | 2023-04-28 | reviewed by expert panel | curation | The NM_000527.5(LDLR):c.1729T>G (p.Trp577Gly) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying evidence codes PS3, PP1_moderate, PM2, PP3, PS4_supporting, PP4, as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: PS3: Level 1 assays: PMID 25378237: Heterologous cells, FACS assays -10-15% LDL-LDLR binding; 5% LDL-LDLR uptake; 5% cell surface LDLR ---- activity is below 70% of wild-type, so functional study is consistent with damaging effect. PP1_moderate: Variant segregates with FH phenotype in at least 4 informative meiosis from 1 family from Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation) PM2: This variant is absent from gnomAD (gnomAD v2.1.1). PP3: REVEL = 0.937. PS4_supporting: Variant meets PM2 and is identified in 2 index cases (1 case with DLCN criteria>=6 from Robarts Research Institute; 1 case with DLCN criteria>=6 from Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation)) PP4: Variant meets PM2 and is identified in 2 index cases who fulfill clinical criteria for FH from several labs (see PS4 for details), after alternative causes of high cholesterol were excluded. |
LDLR- |
RCV000238365 | SCV000295617 | likely pathogenic | Hypercholesterolemia, familial, 1 | 2016-03-25 | criteria provided, single submitter | literature only | |
Robarts Research Institute, |
RCV000238365 | SCV000484700 | likely pathogenic | Hypercholesterolemia, familial, 1 | criteria provided, single submitter | clinical testing | ||
Centre de Génétique Moléculaire et Chromosomique, |
RCV000238365 | SCV000503399 | 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 with co-segregation / Other mutation at same codon/software prediction damaging |
Molecular Genetics Laboratory, |
RCV000238365 | SCV000540895 | likely pathogenic | Hypercholesterolemia, familial, 1 | 2017-01-22 | criteria provided, single submitter | clinical testing | |
Fundacion Hipercolesterolemia Familiar | RCV000238365 | SCV000607632 | pathogenic | Hypercholesterolemia, familial, 1 | 2016-03-01 | criteria provided, single submitter | research |