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]

Link to SEPIO compliant JSON-LD document

Variant: NM_000527.5(LDLR):c.727T>C (p.Cys243Arg)

CA10585105

251425 (ClinVar)

Gene: LDLR

Condition: hypercholesterolemia, familial

Inheritance Mode: Semidominant inheritance

Link to MONDO

UUID: 9e2e98d3-6ac1-41d2-826f-87825e2b6139

HGVS expressions

NM_000527.5:c.727T>C

NM_000527.5(LDLR):c.727T>C (p.Cys243Arg)

NC_000019.10:g.11106597T>C

CM000681.2:g.11106597T>C

NC_000019.9:g.11217273T>C

CM000681.1:g.11217273T>C

NC_000019.8:g.11078273T>C

NG_009060.1:g.22217T>C

ENST00000558518.6:c.727T>C

ENST00000252444.9:n.981T>C

ENST00000455727.6:c.314-795T>C

ENST00000535915.5:c.604T>C

ENST00000545707.5:c.346T>C

ENST00000557933.5:c.727T>C

ENST00000558013.5:c.727T>C

ENST00000558518.5:c.727T>C

ENST00000558528.1:n.242T>C

ENST00000560467.1:n.327T>C

NM_000527.4:c.727T>C

NM_001195798.1:c.727T>C

NM_001195799.1:c.604T>C

NM_001195800.1:c.314-795T>C

NM_001195803.1:c.346T>C

NM_001195798.2:c.727T>C

NM_001195799.2:c.604T>C

NM_001195800.2:c.314-795T>C

NM_001195803.2:c.346T>C

Likely Pathogenic

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

PP4 PP3 PM1 PM2 PS4_Supporting

Evidence Links 0

Expert Panel

Familial Hypercholesterolemia VCEP

Criteria Specification Information

Criteria Specification: ClinGen Familial Hypercholesterolemia Expert Panel Specifications to the ACMG/AMP Variant Classification Guidelines Version 1.2

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Familial Hypercholesterolemia VCEP

The NM_000527.5(LDLR):c.727T>C (p.Cys243Arg) variant is classified as likely pathogenic for Familial Hypercholesterolemia by applying evidence code PM1, PM2, PP3, PP4 and PS4_Supporting 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: PM2 - This variant is absent from gnomAD (gnomAD v2.1.1). PP3 - REVEL = 0.966 PM1 - Variant meets PM2 and alters Cys243, one of the cysteine residues listed. PS4_Supporting - Variant meets PM2 and is identified in 2 index cases who fullfill DLCN≥6 criteria for FH from Research Lab of Molecular Genetics of Lipid Metabolism and PMID: 28502510. PP4 - Variant meets PM2 and is identified in 2 index cases who fullfill DLCN≥6 criteria for FH from Research Lab of Molecular Genetics of Lipid Metabolism after alternative cause of high cholesterol were excluded.

PP4

Variant meets PM2 and is identified in 2 index cases who fullfill DLCN≥6 criteria for FH from Research Lab of Molecular Genetics of Lipid Metabolism after alternative cause of high cholesterol were excluded.

PP3

REVEL = 0.966

PM1

Variant meets PM2 and alters Cys243, one of the cysteine residues listed.

PM2

This variant is absent from gnomAD (gnomAD v2.1.1).

PS4_Supporting

Variant meets PM2 and is identified in 2 index cases who fullfill DLCN≥6 criteria for FH from Research Lab of Molecular Genetics of Lipid Metabolism and PMID: 28502510.

Approved on: 2023-04-28

Published on: 2023-05-01

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