ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.1186G>C (p.Gly396Arg)

dbSNP: rs879254820
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel RCV001251451 SCV002817158 uncertain significance Hypercholesterolemia, familial, 1 2022-10-28 reviewed by expert panel curation The NM_000527.5 (LDLR):c.1186G>C (p.Gly396Arg) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (PM2, PP3, 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 version 2.1.1). PP4: Variant meets PM2 and is identified in 1 index case who fulfil Simon Broome criteria for definite/possible FH after alternative causes of high cholesterol were excluded. Reported by Miroshnikova et al, National Research Center ”Kurchatov Institute”, Gatchina, Russian Federation, PMID 33269076. PP3: REVEL= 0.702, it is not above 0.75, splicing evaluation required. Functional data on splicing is not available. The variant is predicted affecting splicing process in scenario A, donor site: The variant is located at -3 to +6 bases of canonical donor splicing site of exon 8. Wild type canonical donor motif: TGGGTGAGC, MES: 7.23 Variant canonical donor motif: TGCGTGAGC, MES: 3.45. Var/Wt ratio = 0.48, (< 0.8), met PP3. PS3 not met: Functional data not available. PM5 not met: Three other missense variants in the same codon: NM_000527.5 (LDLR):c.1186G>A (p.Gly396Ser), (ClinVarID 251704), NM_000527.5 (LDLR):c.1187G>T (p.Gly396Val), (ClinVarID 924165), NM_000527.5 (LDLR):c.1187G>A (p.Gly396Asp), (ClinVarID 440630). None is classified as Pathogenic by these guidelines, therefore PM5 is not met.
Laboratory of Human Molecular Genetics, Petersburg Nuclear Physics Institute named by B.P.Konstantinov of NRC "Kurchatov Institute" RCV001251451 SCV001245366 pathogenic Hypercholesterolemia, familial, 1 2020-02-01 criteria provided, single submitter clinical testing

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