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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Variant: NM_000527.5(LDLR):c.530C>T (p.Ser177Leu)

CA023715

3686 (ClinVar)

Gene: LDLR

Condition: hypercholesterolemia, familial

Inheritance Mode: Semidominant inheritance

Link to MONDO

UUID: 50f0c43e-cc4f-40fa-b9f2-0e1dbe5c246a

HGVS expressions

NM_000527.5:c.530C>T

NM_000527.5(LDLR):c.530C>T (p.Ser177Leu)

NC_000019.10:g.11105436C>T

CM000681.2:g.11105436C>T

NC_000019.9:g.11216112C>T

CM000681.1:g.11216112C>T

NC_000019.8:g.11077112C>T

NG_009060.1:g.21056C>T

ENST00000558518.6:c.530C>T

ENST00000252444.9:n.784C>T

ENST00000455727.6:c.314-1956C>T

ENST00000535915.5:c.407C>T

ENST00000545707.5:c.314-1129C>T

ENST00000557933.5:c.530C>T

ENST00000558013.5:c.530C>T

ENST00000558518.5:c.530C>T

ENST00000560467.1:n.130C>T

NM_000527.4:c.530C>T

NM_001195798.1:c.530C>T

NM_001195799.1:c.407C>T

NM_001195800.1:c.314-1956C>T

NM_001195803.1:c.314-1129C>T

NM_001195798.2:c.530C>T

NM_001195799.2:c.407C>T

NM_001195800.2:c.314-1956C>T

NM_001195803.2:c.314-1129C>T

Pathogenic

The Expert Panel has overridden the computationally generated classification - "Uncertain Significance - Conflicting Evidence"

PS4 PS3 PP4 PP3 PM2 PM3 PM1 BS4 PP1_Strong

PS2 PS1 PP2 PM6 PM4 PM5 BA1 BS2 PVS1 BS3 BS1 BP5 BP7 BP2 BP3 BP4 BP1

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.530C>T (p.Ser177Leu) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying evidence codes (PS3, PS4, PM1, PM2, PM3, PP1_Strong, PP3, PP4 and BS4) 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 - PMID: 31578082 - Level 1 assay - Heterologous cells (CHO), FACS assays and CLSM: 65% cell surface LDLR, 10% binding and <2% uptake. PMID: 2760205 - Level 2 assay - Homozygous patient fibroblast, 125I-LDL assays: <2% LDLR activity. PMID: 25647241 - Level 3 assay - Heterologous cells (HeLa), CLSM assays: LDLR activity decreased compared to WT - considered as disruptive. PS4 - Variant meets PM2. Variant identified in 30 unrelated index cases (5 cases (2 with DLCN≥6; 3 with Simon-Broome possible) from Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies (APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière); 1 case with Simon-Broome possible from GeneDx Inc.; 11 cases with Simon-Broome possible from Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge; 13 cases with Simon-Broome possible/definite from Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation). PM1 - Variant meets PM2 and is missense in exon 4. PM2 - PopMax MAF = 0.00006533 (0.006533%) in South Asian exomes+genomes (gnomAD v2.1.1). PM3 - Patient 3 from PMID: 18263977 has LDL = 19.7 mmol/l and also LDLR p.Arg350* in trans - Pathogenic by these guidelines. Two true homozygotes (FHF23 and FHF57) published in PMID: 27816806 had LDL = 16.2 mmol/l and 22.6 mmol/l, respectively. PP1_Strong - Variant segregates with FH phenotype in 52 informative meiosis in 26 families from different labs (Laboratory of Genetics and Molecular Cardiology, University of São Paulo; 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 Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge): 43 relatives tested positive had LDL-C >75th percentile + 9 relatives tested negative had LDL-C <50th percentile. PP3 - REVEL = 0.886. PP4 - Variant meets PM2. Variant identified in 30 unrelated index cases who fulfill clinical criteria for FH from several labs (see PS4 for details). BS4 - Variant does not segregate with phenotype in 14 informative meiosis from at least 6 families from different labs (Laboratory of Genetics and Molecular Cardiology, University of São Paulo; Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation); Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge): 13 relatives tested negative but had LDL-C >75th percentile + 1 relative tested positive but LDL-C <50th percentile. Variant has 3 Strong, 3 Moderate and 2 Supporting evidence codes towards Pathogenic, enough to classify as Pathogenic, and only 1 Strong evidence codes towards Benign. The Pathogenic criteria overwhelms the Benign criteria, so we are confident in classifying this variant as Pathogenic.

PS4

Variant meets PM2. Variant identified in 30 unrelated index cases (5 cases (2 with DLCN≥6; 3 with Simon-Broome possible) from Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies (APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière); 1 case with Simon-Broome possible from GeneDx Inc.; 11 cases with Simon-Broome possible from Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge; 13 cases with Simon-Broome possible/definite from Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation).

PS3

PMID: 31578082 - Level 1 assay - Heterologous cells (CHO), FACS assays and CLSM: 65% cell surface LDLR, 10% binding and <2% uptake. PMID: 2760205 - Level 2 assay - Homozygous patient fibroblast, 125I-LDL assays: <2% LDLR activity. PMID: 25647241 - Level 3 assay - Heterologous cells (HeLa), CLSM assays: LDLR activity decreased compared to WT - considered as disruptive.

PP4

PP3

REVEL = 0.886

PM2

PopMax MAF = 0.00006533 (0.006533%) in South Asian exomes+genomes (gnomAD v2.1.1).

PM3

Patient 3 from PMID: 18263977 has LDL = 19.7 mmol/l and also LDLR p.Arg350* in trans - Pathogenic by these guidelines. Two true homozygotes (FHF23 and FHF57) published in PMID: 27816806 had LDL = 16.2 mmol/l and 22.6 mmol/l, respectively.

PM1

Variant meets PM2 and is missense in exon 4.

BS4

Variant does not segregate with phenotype in 14 informative meiosis from at least 6 families from different labs (Laboratory of Genetics and Molecular Cardiology, University of São Paulo; Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation); Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge): 13 relatives tested negative but had LDL-C >75th percentile + 1 relative tested positive but LDL-C <50th percentile.

PP1_Strong

Variant segregates with FH phenotype in 52 informative meiosis in 26 families from different labs (Laboratory of Genetics and Molecular Cardiology, University of São Paulo; 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 Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge): 43 relatives tested positive had LDL-C >75th percentile + 9 relatives tested negative had LDL-C <50th percentile.

PS2