ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.1598G>A (p.Trp533Ter)

dbSNP: rs746939188
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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 RCV000237191 SCV002568024 pathogenic Hypercholesterolemia, familial, 1 2022-08-28 reviewed by expert panel curation The NM_000527.5(LDLR):c.1598G>A (p.Trp533Ter) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying evidence codes PVS1, PM2, PP4 and PS4_Supporting 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: PVS1 - variant is nonsense upstream of amino acid 830, so PVS1 is met. PM2 - PopMax MAF = 0.000008792 (0.0009%) in European Non-Finnish exomes (gnomAD v2.1.1). It is below 0.02%, so PM2 is met. PP4 - variant meets PM2. identified in: - 1 index case who fulfills SB criteria from Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge. - 1 index case who fulfills SB criteria from Marduel et al. 2010 (PMID: 20809525). so PP4 is met. PS4_supporting - variant meets PM2 and was identified in 2 unrelated index cases from different labs (please see PP4 for details), so PS4_Supporitng is met.
LDLR-LOVD, British Heart Foundation RCV000237191 SCV000295529 pathogenic Hypercholesterolemia, familial, 1 2016-03-25 criteria provided, single submitter literature only
Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge RCV000237191 SCV000322962 uncertain significance Hypercholesterolemia, familial, 1 2016-03-01 criteria provided, single submitter research 0/190 non-FH alleles
Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix RCV000237191 SCV000503373 pathogenic Hypercholesterolemia, familial, 1 2016-12-16 criteria provided, single submitter clinical testing subject mutated among 2600 FH index cases screened = 1
Labcorp Genetics (formerly Invitae), Labcorp RCV001854903 SCV002145536 pathogenic Familial hypercholesterolemia 2021-03-07 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Trp533*) in the LDLR gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in LDLR are known to be pathogenic (PMID: 20809525, 28645073). For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. This variant has been observed in individual(s) with clinical features of familial hypercholesterolemia or myocardial infarction (PMID: 20809525, 25487149). ClinVar contains an entry for this variant (Variation ID: 251926). This variant is present in population databases (rs746939188, ExAC 0.002%).

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