ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.2389+2T>G

dbSNP: rs879255188
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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 RCV000238361 SCV002568020 pathogenic Hypercholesterolemia, familial, 1 2022-08-28 reviewed by expert panel curation The NM_000527.5(LDLR):c.2389+2T>G variant is classified as Pathogenic for Familial Hypercholesterolemia by applying evidence codes PVS1_Strong, PP1_moderate, PM2, PP4 and PS4_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: PVS1_strong - variant is at +2 donor splice site, and is predicted to lead to exon 16 skipping. Exon 16 is in frame, so PVS1_Strong is met. PP1_moderate - variant segregates with FH phenotype in 5 relatives from Robarts Research Institute, so PP1_Moderate is met. PM2 - This variant was not identified in gnomAD (gnomAD v2.1.1), so PM2 is met. PS4_Supporting - variant meets PM2 and is identified in 3 unrelated index cases, after alternative causes of hypercholesterolemia were excluded, from different labs (1 with DLCN >=6 from Robarts Research Institute, 1 with possible FH according to Simon-Broome criteria from PMID 17539906 (UK) and 1 with DLCN >=6 from PMID 33418990 (Russia)), so PS4_Supporting is met. PP4 - variant meets PM2 and is identified in 3 unrelated index cases from different labs (see PS4 for details), so PP4 is met.
LDLR-LOVD, British Heart Foundation RCV000238361 SCV000295972 likely pathogenic Hypercholesterolemia, familial, 1 2016-03-25 criteria provided, single submitter literature only
Robarts Research Institute, Western University RCV000238361 SCV000484794 likely pathogenic Hypercholesterolemia, familial, 1 criteria provided, single submitter clinical testing
Brunham Lab, Centre for Heart and Lung Innovation, University of British Columbia RCV000238361 SCV001432565 pathogenic Hypercholesterolemia, familial, 1 2019-01-21 criteria provided, single submitter research

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