ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.889A>C (p.Asn297His)

gnomAD frequency: 0.00001  dbSNP: rs879254709
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel RCV000238042 SCV002506369 uncertain significance Hypercholesterolemia, familial, 1 2022-02-28 reviewed by expert panel curation The NM_000527.5(LDLR):c.889A>C (p.Asn297His) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes PM2, PS4_supporting 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 - PopMax MAF = 1/24948 = 0.00004 (0.004%) in African/African-American 8692 exomes plus 16256 genomes (gnomAD v2.1.1), so PM2 is Met. PS4_supporting - Variant meets PM2 and is identified in at least 1 index case with DLCN>6 (definite heterozygous hypercholesterolemia) from The Netherlands (PMID: 16250003) and at least 1 index case with DLCN>6 from Spain (PMID: 19318025), so PS4_Supporting is Met. PP4 - Variant meets PM2 and is identified in at least 1 index case with DLCN>6 (definite heterozygous hypercholesterolemia) from The Netherlands (PMID: 16250003) and at least 1 index case with DLCN>6 from Spain (PMID: 19318025), so PP4 is Met.
LDLR-LOVD, British Heart Foundation RCV000238042 SCV000295032 uncertain significance Hypercholesterolemia, familial, 1 2016-03-25 criteria provided, single submitter literature only
Fundacion Hipercolesterolemia Familiar RCV000238042 SCV000607513 uncertain significance Hypercholesterolemia, familial, 1 2016-03-01 criteria provided, single submitter research
GeneDx RCV003126648 SCV003803360 uncertain significance not provided 2022-08-05 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 19318025, 16250003)
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum RCV000238042 SCV000606260 pathogenic Hypercholesterolemia, familial, 1 no assertion criteria provided research

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