ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.261G>A (p.Trp87Ter)

dbSNP: rs199570811
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel RCV000238280 SCV001960957 pathogenic Hypercholesterolemia, familial, 1 2021-06-07 reviewed by expert panel curation The NM_000527.5(LDLR):c.261G>A (p.Trp87Ter) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying evidence codes (PVS1, PS4, PM2, PP4 and PS3_Supporting) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755). The supporting evidence is as follows: PVS1 - Variant is nonsense, causing a premature stop at codon 87. It is upstream of amino acid 830, so PVS1 is Met. PS4 - Variant meets PM2. Identified in 10 FH index cases with Dutch Lipid Clinical Network score 10.3 ± 4.1 (Mean ± standard deviation of DLCN score) from PMID: 21990180. PM2 - No population data was found for this variant in gnomAD (gnomAD v2.1.1). PP4 - Variant meets PM2. Identified in 10 FH index cases with Dutch Lipid Clinical Network score 10.3 ± 4.1 (Mean ± standard deviation of DLCN score) from PMID: 21990180. PS3_supporting - Level 3 assays: PMID 21990180: Htz patient lymphocytes, FACS and CLSM assays - results - FACS: 40% cell surface LDLR; 60% LDL-LDLR binding; 75% uptake, CLSM: 50-60% cell surface LDLR and LDL-LDLR binding ---- Results are below 85% of wild-type, so PS3_supporting is Met
LDLR-LOVD, British Heart Foundation RCV000238280 SCV000294563 pathogenic Hypercholesterolemia, familial, 1 2016-03-25 criteria provided, single submitter literature only
Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge RCV000238280 SCV000322882 pathogenic Hypercholesterolemia, familial, 1 2016-03-01 criteria provided, single submitter research
Fundacion Hipercolesterolemia Familiar RCV000238280 SCV000607436 pathogenic Hypercholesterolemia, familial, 1 2016-03-01 criteria provided, single submitter research
CeGaT Center for Human Genetics Tuebingen RCV003326386 SCV004033637 pathogenic not provided 2023-07-01 criteria provided, single submitter clinical testing LDLR: PVS1, PM2, PP4:Moderate, PS4:Moderate, PS3:Supporting
Labcorp Genetics (formerly Invitae), Labcorp RCV005090202 SCV005838006 pathogenic Familial hypercholesterolemia 2024-08-08 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Trp87*) in the LDLR gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in LDLR are known to be pathogenic (PMID: 20809525, 28645073). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with LDLR-related conditions (PMID: 19318025, 34456049). ClinVar contains an entry for this variant (Variation ID: 251100). For these reasons, this variant has been classified as Pathogenic.
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum RCV000238280 SCV000606052 pathogenic Hypercholesterolemia, familial, 1 no assertion criteria provided research

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