ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.1856T>G (p.Phe619Cys)

dbSNP: rs879255054
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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 RCV000238087 SCV002506394 likely pathogenic Hypercholesterolemia, familial, 1 2022-02-10 reviewed by expert panel curation The NM_000527.5 (LDLR): c.1856T>G (p.Phe619Cys) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying evidence codes (PM2, PP3, PP4, PS4_Supporting, PP1) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines ( The supporting evidence is as follows: PM2 Met: This variant is absent in gnomAD (gnomAD v2.1.1). PP3 Met: REVEL = 0.856, which is above the threshold of 0.75. PP4 Met: This variant meets PM2 and is identified >1 index cases who met clinical criteria for FH after alternative causes for high cholesterol were excluded. PS4_Supporting Met: Variant meets PM2, and is identified in 2 unrelated index cases who fulfil DLCN criteria for FH diagnosis from different labs. One index case is from U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille (SCV000583897.1), another index case is reported from Department of Vascular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands (PMID16250003, SCV000295717.2). PP1 Met: Variant segregates with FH phenotype in 2 informative meiosis in one family reported from U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille (SCV000583897.1). There are two other variants in same codon: LDLR: NM_000527:c.1855T>C (p.Phe619Leu), LDLR: NM_000527:c.1856T>C (p.Phe619Ser), which are classified as Likely Pathogenic by these guidelines. Neither variant is classified as Pathogenic, therefore PM5 is not met.
LDLR-LOVD, British Heart Foundation RCV000238087 SCV000295717 likely pathogenic Hypercholesterolemia, familial, 1 2016-03-25 criteria provided, single submitter literature only
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille RCV000238087 SCV000583897 pathogenic Hypercholesterolemia, familial, 1 2017-03-30 criteria provided, single submitter clinical testing
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum RCV000238087 SCV000606543 pathogenic Hypercholesterolemia, familial, 1 no assertion criteria provided research

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