Evidence Repository - Clinical Genome Resources

The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

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226329 (ClinVar)

Gene: LDLR

Condition: hypercholesterolemia, familial

Inheritance Mode: Semidominant inheritance

Link to MONDO

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

PP1_Strong PS4 PP4 PM4 PS3_Moderate PM2

BA1 BS2 BS4 BS3 BS1 BP2 BP3 BP4 BP1 BP5 BP7 PS2 PS1 PP3 PP2 PM1 PM3 PM5 PM6 PVS1

Evidence Links 0

Expert Panel

Familial Hypercholesterolemia VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

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.

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.

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.

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.

PM4

Variant meets PM2 and is in frame deletion.

PS3_Moderate

PMID: 2088165 - Level 2 assay - Homozygous patients' fibroblasts, 125I-LDL assays: <2% LDLR activity.

PM2

PopMax MAF = 0.000008826 (0.0008826%) in European (non-Finnish) exomes+genomes (gnomAD v2.1.1).

BA1