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.-140C>G

CA10584703

250949 (ClinVar)

Gene: N/A

Condition: hypercholesterolemia, familial

Inheritance Mode: Semidominant inheritance

Link to MONDO

UUID: fbf0a970-dfc1-4b63-85e6-1c7324510eba

HGVS expressions

NM_000527.4(LDLR):c.-140C>G

NC_000019.10:g.11089409C>G

CM000681.2:g.11089409C>G

NC_000019.9:g.11200085C>G

CM000681.1:g.11200085C>G

NC_000019.8:g.11061085C>G

NG_009060.1:g.5029C>G

ENST00000558518.5:c.-140C>G

NM_000527.4:c.-140C>G

NM_001195798.1:c.-140C>G

NM_001195799.1:c.-140C>G

NM_001195800.1:c.-140C>G

NM_001195803.1:c.-140C>G

NR_163945.1:n.251G>C

Uncertain Significance

PS3_Moderate PM2

PS4 BP7

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.-140C>G 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 (v2.1.1). PS3_Mderate : Level 3 assay: PMID:21538688, Hep G2 cell, luciferase reporter gene assay. HepG2 transfection experiments resulted in a residual LDLR transcriptional activity of 7%. The authors also performed electrophoresis mobility shift assays (EMSA), with reference to De Castro et al., 2011; PMID 20884100), which assess if a variant alters promoter protein binding properties (rather unspecifically, however). Although, no mention of any validation control or number of repeats in publication source is available, this variant showed a 25% reduction band intensity compared to WT (i.e. some degree of altered binding properties). These results were confirmed by Kircher M et al (PMID: 31395865).

PS3_Moderate

Level 3 assay: PMID:21538688, Hep G2 cell, luciferase reporter gene assay. HepG2 transfection experiments resulted in a residual LDLR transcriptional activity of 7%. The authors also performed electrophoresis mobility shift assays (EMSA), with reference to De Castro et al., 2011; PMID 20884100), which assess if a variant alters promoter protein binding properties (rather unspecifically, however). Although, no mention of any validation control or number of repeats in publication source is available, this variant showed a 25% reduction band intensity compared to WT (i.e. some degree of altered binding properties). These results were confirmed by Kircher M et al (PMID: 31395865).

PM2

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

PS4

The variant is reported in PMID: 21538688 and PMID: 19318025. In PMID: 21538688 authors reported screening of 3,705 unrelated individuals clinically diagnosed as definitive, probable, or possible FH based on the Dutch MedPed criteria but single's patient data are not available. In PMID: 19318025 authors reported 808 unrelated cases with clinical diagnosis of FH and DLCN>/6 after the application of the Dutch Lipid Clinic Network criteria but single's patient data are not available.

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

Approved on: 2022-10-28

Published on: 2022-12-24

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