ClinVar Miner

Submissions for variant NC_000019.10:g.11089413C>G

dbSNP: rs879254374
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel RCV000237183 SCV002568021 uncertain significance Hypercholesterolemia, familial, 1 2022-08-28 reviewed by expert panel curation The NM_000527.4(LDLR):c.-136C>G variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes PM2, PS3_Moderate and PP4 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), so PM2 is met. PS3_moderate - 2 Level 3 FS: (1) De Castro-Orós et al. 2011 (PMID: 21538688): Heterologous cells (HepG2), luciferase assays - results: 12% reporter gene expression (2) Kircher et al. 2019 (PMID: 31395865): saturation mutagenesis in HepG2 cells, luciferase high throughput study - results: 16% and 11% luciferase expression --- in both studies, transcription levels are below 50% of wild-type, so PS3_Moderate is met. PP4 - Variant meets PM2 and is identified in 1 index case who fulfills DLCN >6 criteria for FH from PMID: 21538688, after alternative causes of high cholesterol were excluded.
LDLR-LOVD, British Heart Foundation RCV000237183 SCV000294391 likely pathogenic Hypercholesterolemia, familial, 1 2016-03-25 criteria provided, single submitter literature only
Fundacion Hipercolesterolemia Familiar RCV000237183 SCV000607393 uncertain significance Hypercholesterolemia, familial, 1 2016-03-01 criteria provided, single submitter research
Labcorp Genetics (formerly Invitae), Labcorp RCV003581590 SCV004298005 likely pathogenic Familial hypercholesterolemia 2023-09-17 criteria provided, single submitter clinical testing Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the -136C nucleotide in the LDLR gene. Other variant(s) that disrupt this nucleotide have been determined to be pathogenic (PMID: 7937987, 8664911, 15199436, 15359125, 16250003). This suggests that this nucleotide is clinically significant, and that variants that disrupt this position are likely to be disease-causing. Experimental studies have shown that this variant affects LDLR function (PMID: 21538688). ClinVar contains an entry for this variant (Variation ID: 250954). This variant has been observed in individuals with clinical features of familial hypercholesterolemia (PMID: 21538688; Invitae). This variant is not present in population databases (gnomAD no frequency). This variant occurs in a non-coding region of the LDLR gene. It does not change the encoded amino acid sequence of the LDLR protein.

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