Variant: NM_000527.4(LDLR):c.-187_-185del

CA645509248

438314 (ClinVar)

Gene: N/A

Condition: hypercholesterolemia, familial

Inheritance Mode: Semidominant inheritance

UUID: 86c86059-5846-4a77-ad34-089d165c8f16

Approved on: 2023-04-28

Published on: 2024-10-02

HGVS expressions

NM_000527.4(LDLR):c.-187_-185del
NC_000019.10:g.11089362_11089364del
CM000681.2:g.11089362_11089364del
NC_000019.9:g.11200038_11200040del
CM000681.1:g.11200038_11200040del
NC_000019.8:g.11061038_11061040del
NG_009060.1:g.4982_4984del
NR_163945.1:n.302_304del

Uncertain Significance

• Met criteria codes: PM2 PS3_Supporting

• Not Met criteria codes: BP2 PP4

Expert Panel

Familial Hypercholesterolemia VCEP

Criteria Specification Information

Evidence submitted by expert panel

Familial Hypercholesterolemia VCEP

The NM_000527.5 (LDLR):c.-187_185del variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2 and PS3_Supporting as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 28 April 2023. The supporting evidence is as follows: PM2: This variant is absent from gnomAD (gnomAD version 2.1.1). PS3_Supporting: Level 3 experiment, heterologous cells (HepG2) were used for luciferase assays, 8% reporter gene expression observed, PMID 9610768 (Peeters et al., 1998).

Met criteria codes

• PM2: This variant is absent from gnomAD (gnomAD version 2.1.1).
• PS3_Supporting: Level 3 experiment, heterologous cells (HepG2) were used for luciferase assays, 8% reporter gene expression observed, published by Peeters et al., 1998, PMID 9610768.

Not Met criteria codes

• BP2: Variant identified in an index case with heterozygous FH phenotype (LDL-C 7.69 mmol/l) and NM_000527.5 (LDLR):c.172delG (p.Glu58fs), classified as Pathogenic by these guidelines. However two variants were not confirmed in trans, reported by Peeters et al, 1998, PMID 9610768.
• PP4: Variant meets PM2 and is identified in 1 index case who fulfil DLCN definite FH criteria with heterozygous phenotype, reported by van Wingerden, 1981, Department of Medicine, Groothoek Hospital, Lebowa, PMID 7280910. However, this patient with heterozygous FH phenotype also carries pathogenic LDLR: c.172delG (p.Glu58fs) which alone could explain the phenotype, reported by Peeters et al, 1998, PMID 9610768.