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_000527.4(LDLR):c.-138T>C

CA10584706

250952 (ClinVar)

Gene: LDLR

Condition: hypercholesterolemia, familial

Inheritance Mode: Semidominant inheritance

Link to MONDO

UUID: a7eeabdf-37f5-4de1-b494-d7efd05bf01f

HGVS expressions

NM_000527.4:c.-138T>C

NM_000527.4(LDLR):c.-138T>C

NC_000019.10:g.11089411T>C

CM000681.2:g.11089411T>C

NC_000019.9:g.11200087T>C

CM000681.1:g.11200087T>C

NC_000019.8:g.11061087T>C

NG_009060.1:g.5031T>C

ENST00000558518.5:c.-138T>C

NM_001195798.1:c.-138T>C

NM_001195799.1:c.-138T>C

NM_001195800.1:c.-138T>C

NM_001195803.1:c.-138T>C

NR_163945.1:n.249A>G

Uncertain Significance

PM2 PS3_Supporting

PS4 BP7 BS4

Evidence Links 0

Expert Panel

Familial Hypercholesterolemia VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Familial Hypercholesterolemia VCEP

The NM_000527.4(LDLR):c.-138T>C variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (PM2, PS3_supporting) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755). The supporting evidence is as follows: PM2_Met : This variant is absent from gnomAD (v.2.1.1). PS3_supporting Met: Level 3 Assay: Luciferase Assay + COS cells. The variant T-45C (Hobbs' numbering: -45T>C) is in the proximal Sp1 binding site in repeat 3 of the 42 bp region of the promoter required for steroldependent regulation of transcription. In 1995 Sun et al ( PMID: 8589690) reported that the variant reduced transcriptional activity to approximately 43% of normal in the presence, and 25% in the absence of sterols in the medium (repressing variant).

PM2

This variant is absent from gnomAD (v.2.1.1).

PS3_Supporting

Level 3 Assay: Luciferase Assay + COS cells. The variant T-45C (Hobbs' numbering: -45T>C) is in the proximal Sp1 binding site in repeat 3 of the 42 bp region of the promoter required for steroldependent regulation of transcription. In 1995 Sun et al ( PMID: 8589690) reported that the variant reduced transcriptional activity to approximately 43% of normal in the presence, and 25% in the absence of sterols in the medium (repressing variant).

PS4

only 1 proband was found as carrier of the variant but no information on DLCN score or SB are reported. The proband shows Total Cholesterol levels=8.5 mmol/L

BP7

This is a promoter variant. Splicing evaluation required. Functional data on splicing not available. A. Not on limits B. Not on limits C. Not on limits

BS4

The variant does not segregate in 1 proband's mother and 5 siblings. All these individuals were not significantly hypercholesterolaemic. The mother shows TC=5.6 mmol/L, The 5 sibling show TC=7.5 mmol/L, TC=5.5 mmol/L, TC=6.3 mmol/L, TC=7.4 mmol/L, TC=6.9 mmol/L

Approved on: 2022-10-28

Published on: 2022-12-24

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