The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries.
[Disclaimer]
- Gene obtained from curated document aligns with ClinVar but not with the Allele Registry data
- 'cspec' property is found but contains no ID!
- No Criteria Specification was provided in the publication event for the variant classifaction.
- The Criteria Specification shown below is a best-estimate based on the VCEP, gene, disease, and publication date.
226329 (ClinVar)
Gene: LDLR
Condition: hypercholesterolemia, familial
(MONDO:0007750)
Inheritance Mode: Semidominant inheritance
UUID: f93a6a4d-f43a-4d61-ab69-e4a067024147
Approved on: 2022-06-02
Published on: 2022-06-30
HGVS expressions
NM_000527.5:c.651TGG[1]
NM_000527.5(LDLR):c.651TGG[1] (p.Gly219del)
Pathogenic
Met criteria codes 6
PS3_Moderate
PP1_Strong
PS4
PP4
PM2
PM4
Not Met criteria codes 20
PVS1
BS2
BS4
BS3
BS1
BP5
BP7
BP2
BP3
BP4
BP1
PS2
PS1
PP3
PP2
BA1
PM6
PM1
PM3
PM5
Evidence Links 0
Expert Panel
Evidence submitted by expert panel
Familial Hypercholesterolemia VCEP
NM_000527.5(LDLR):c.651TGG[1] (p.Gly219del) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying evidence codes (PP1_strong, PS3_moderate, PS4, PM2, PM4 and 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:
PP1_strong - Variant segregates with phenotype in 9 informative meiosis in 5 families from different labs (Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies (APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière); Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation); Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA)): 9 affected family members have the variant.
PS3_moderate - PMID: 2088165 - Level 2 assay - Homozygous patients' fibroblasts, 125I-LDL assays: <2% LDLR activity.
PS4 - Variant meets PM2. Variant identified in 10 unrelated index cases (1 case with DLCN ≥ 6 from Robarts Research Institute; 2 cases with DLCN ≥ 6 from Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies (APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière); 4 cases with Simon Broome possible/definite FH from Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation); 1 case with DLCN ≥ 6 from Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA); 2 cases with Simon Broome possible/definite FH from GeneDx Inc.
PM2 - PopMax MAF = 0.000008826 (0.0008826%) in European (non-Finnish) exomes+genomes (gnomAD v2.1.1).
PM4 - Variant meets PM2 and is in frame deletion.
PP4 - Variant meets PM2. Identified in 4 FH case from Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation) with clinical Simon Broome possible/definite FH, after alternative causes of high cholesterol were excluded.
Met criteria codes
PMID: 2088165 - Level 2 assay - Homozygous patients' fibroblasts, 125I-LDL assays: <2% LDLR activity.
Variant segregates with phenotype in 9 informative meiosis in 5 families from different labs (Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies (APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière); Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation); Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA)): 9 affected family members have the variant.
Variant meets PM2. Variant identified in 10 unrelated index cases (1 case with DLCN ≥ 6 from Robarts Research Institute; 2 cases with DLCN ≥ 6 from Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies (APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière); 4 cases with Simon Broome possible/definite FH from Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation); 1 case with DLCN ≥ 6 from Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA); 2 cases with Simon Broome possible/definite FH from GeneDx Inc.
Variant meets PM2. Identified in 4 FH case from Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation) with clinical Simon Broome possible/definite FH, after alternative causes of high cholesterol were excluded.
Not Met criteria codes
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
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No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
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