ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.1729T>G (p.Trp577Gly)

dbSNP: rs879255000
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel 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-LOVD, British Heart Foundation RCV000238365 SCV000295617 likely pathogenic Hypercholesterolemia, familial, 1 2016-03-25 criteria provided, single submitter literature only
Robarts Research Institute, Western University RCV000238365 SCV000484700 likely pathogenic Hypercholesterolemia, familial, 1 criteria provided, single submitter clinical testing
Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix 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, Centre for Cardiovascular Surgery and Transplantation 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

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