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.81C>G (p.Cys27Trp)

CA041664

226304 (ClinVar)

Gene: LDLR

Condition: hypercholesterolemia, familial

Inheritance Mode: Semidominant inheritance

Link to MONDO

UUID: 1b6349ea-5843-44ac-bd0b-6dbe58fb0da4

HGVS expressions

NM_000527.5:c.81C>G

NM_000527.5(LDLR):c.81C>G (p.Cys27Trp)

NC_000019.10:g.11100236C>G

CM000681.2:g.11100236C>G

NC_000019.9:g.11210912C>G

CM000681.1:g.11210912C>G

NC_000019.8:g.11071912C>G

NG_009060.1:g.15856C>G

ENST00000558518.6:c.81C>G

ENST00000252444.9:n.335C>G

ENST00000455727.6:c.81C>G

ENST00000535915.5:c.81C>G

ENST00000545707.5:c.81C>G

ENST00000557933.5:c.81C>G

ENST00000557958.1:n.167C>G

ENST00000558013.5:c.81C>G

ENST00000558518.5:c.81C>G

ENST00000560502.5:n.167C>G

NM_000527.4:c.81C>G

NM_001195798.1:c.81C>G

NM_001195799.1:c.81C>G

NM_001195800.1:c.81C>G

NM_001195803.1:c.81C>G

NM_001195798.2:c.81C>G

NM_001195799.2:c.81C>G

NM_001195800.2:c.81C>G

NM_001195803.2:c.81C>G

Pathogenic

PS3_Moderate PS4 PP1 PP4 PP3 PM2 PM1

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.81C>G (p.Cys27Trp) variant is classified as pathogenic for Familial Hypercholesterolemia by applying evidence code PM1, PM2, PS3_moderate, PS4, PP1, PP3 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: PM1: Variant meets PM2 and alters Cys27, one of the cysteine residues listed. PM2: PopMax MAF = 0.00003518 (0.004%) in European (non-Finnish) exomes (gnomAD v2.1.1). PS3_moderate: PMID:1301956 - Level 2 assay - study on hmz patient's fibroblast cell, LDLR activity value range: 15-30%. PS4: Variant meets PM2. Variant identified in >15 index cases - 1 case from Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation) with Simon Broome possible - 1 case from Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA) with Dutch lipid clinic network >=6 - 2 cases from Robarts Research Institute with Dutch lipid clinic network >=6 - 2 cases from Research Lab of Molecular Genetics of Lipid Metabolism - Prof. M.Arca with Dutch lipid clinic network >=6 -as well as >10 cases from (PMID: 1301956, 9259195, 11317361, 11668627, 14974088, 16250003, 23375686, 25463123, 27497240, 27824480, 31345425) PP1: Variant segregates with FH phenotype in at least 2 informative meiosis (minimum 2) from 2 families from different labs (Research Lab of Molecular Genetics of Lipid Metabolism - Prof. M.Arca, and Laboratory of Genetics and Molecular Cardiology) PP3: REVEL = 0.759 PP4: Variant meets PM2 and is identified in several index case who fulfil SB/DLCN>6/MedPed/other criteria for FH from different labs (see PS4), after alternative causes of high cholesterol were excluded.

PS3_Moderate

Study of at least one part of the whole LDLR cycle in homozygous patient cultured cells resulting in 15-30% LDLR activity (PMID: 1301956).

PS4

Variant meets PM2 and is identified in at >15 unrelated index cases who fulfil clinical criteria for FH (1 case from Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation) or DLCN > 6 ( 1 case from Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA); 2 cases from Robarts Research Institute; 2 cases from Research Lab of Molecular Genetics of Lipid Metabolism - Prof. M.Arca) -as well as >10 cases from (PMID: 1301956, 9259195, 11317361, 11668627, 14974088, 16250003, 23375686, 25463123, 27497240, 27824480, 31345425)

PP1

Variant segregates with FH phenotype in at least 2 informative meiosis (minimum 2) from 2 families from different labs (Research Lab of Molecular Genetics of Lipid Metabolism - Prof. M.Arca, and Laboratory of Genetics and Molecular Cardiology)

PP4

Variant meets PM2 and is identified in several index cases who fulfil SB/DLCN>6/MedPed/other criteria for FH from different labs (see PS4), after alternative causes of high cholesterol were excluded.

PP3

REVEL = 0.759. It is above 0.75

PM2

PopMax MAF = 0.00004 (0.004%) in European non-Finnish exomes (gnomAD v2.1.1).

PM1

Variant meets PM2 and is located in highly conserved Cystein 27.

Approved on: 2022-05-06

Published on: 2022-12-24

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