ClinVar Miner

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

dbSNP: rs875989887
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel RCV000237955 SCV002817161 uncertain significance Hypercholesterolemia, familial, 1 2022-10-28 reviewed by expert panel curation 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).
LDLR-LOVD, British Heart Foundation RCV000237955 SCV000294384 likely pathogenic Hypercholesterolemia, familial, 1 2016-03-25 criteria provided, single submitter literature only
Fundacion Hipercolesterolemia Familiar RCV000237955 SCV000607392 uncertain significance Hypercholesterolemia, familial, 1 2016-03-01 criteria provided, single submitter research

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