ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.2099A>G (p.Asp700Gly)

dbSNP: rs879255139
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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 RCV000237371 SCV002506377 likely pathogenic Hypercholesterolemia, familial, 1 2022-03-25 reviewed by expert panel curation The NM_000527.5(LDLR):c.2099A>G (p.Asp700Gly) variant is classified as Likely pathogenic for Familial Hypercholesterolemia by applying evidence codes PS3, PS4_Supporting, PM2, PP3 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: PS3 - Level 1 assays: PMID 32015373: Heterologous cells (CHO), FACS assays - result - 35% cell surface LDLR, 60% binding and 52% uptake. ---- activity is below 70% of wild-type, so PS3 is Met. PS4_Supporting - Variant meets PM2 and is identified in 2 unrelated index cases: 1 index case with FH criteria (CT>95th percentile, plus tendon xanthomata or pCHD in proband or 1st degree and hypercholesterolemia in family) from Spain (PMID: 11668640) and at least 1 index case with SB criteria for FH from China (PMID: 22353362), so PS4_Supporting is Met. PM2 - This variant is absent from gnomAD (gnomAD v2.1.1), so PM2 is Met. PP3 - REVEL = 0.875. It is above 0.75, so PP3 is Met. PP4 - Variant meets PM2 and is identified in 2 unrelated index cases who fulfill clinical criteria for FH from several labs (see PS4 for details), so PP4 is Met.
LDLR-LOVD, British Heart Foundation RCV000237371 SCV000295873 likely pathogenic Hypercholesterolemia, familial, 1 2016-03-25 criteria provided, single submitter literature only
Fundacion Hipercolesterolemia Familiar RCV000237371 SCV000607676 uncertain significance Hypercholesterolemia, familial, 1 2016-03-01 criteria provided, single submitter research
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde,Academisch Medisch Centrum RCV000237371 SCV000606598 pathogenic Hypercholesterolemia, familial, 1 no assertion criteria provided research

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