ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.1301C>G (p.Thr434Arg)

dbSNP: rs745343524
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel RCV000237295 SCV002817149 pathogenic Hypercholesterolemia, familial, 1 2022-10-28 reviewed by expert panel curation The NM_000527.5(LDLR):c.1301C>G (p.Thr434Arg) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying evidence codes PS4, PM2, PM3, PP1_Strong, 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: PS4: Variant meets PM2 and is identified in 10 unrelated cases, as follows: 6 patients with DLCN >=6 and 2 patients with Simon-Broome criteria of possible FH from Centre de Genetique Moleculaire et Chromosomique, Unite de genetique de l'Obesite et des Dyslipidies; 1 case with MedPed criteria from PMID 21868016 (Garcia-Garcia et al., 2011); 1 case with DLCN>6 from PMID 10634824 (Deiana et al., 2000). So PS4 is met. PM2: This variant is absent from gnomAD (gnomAD v2.1.1), so PM2 is met. PM3: Variant meets PM2 and is identified in 2 siblings from PMID 29306853 with childhood total cholesterol levels >700 mg/dL and homozygous for this variant. So PM3 is met. PP1_Strong: Variant segregates with FH phenotype in >1 families, as follows: 6 affected family members from Centre de Genetique Moleculaire et Chromosomique, Unite de genetique de l'Obesite et des Dyslipidies; 10 affected members tested positive and 7 unaffected members tested negative in one family in 17 informative meiosis from PMID 21868016, so PP1_Strong is met. PP4: Variant meets PM2 and is identified in 10 unrelated index cases who fulfill clinical criteria for FH (see PS4 for details).
LDLR-LOVD, British Heart Foundation RCV000237295 SCV000295353 uncertain significance Hypercholesterolemia, familial, 1 2016-03-25 criteria provided, single submitter literature only
Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix RCV000237295 SCV000503330 likely pathogenic Hypercholesterolemia, familial, 1 2016-12-16 criteria provided, single submitter clinical testing subjects mutated among 2600 FH index cases screened = 7 , family members = 4 with unclear co-segregation in 1 family / FH-Sassari-4/Software predictions: Benign
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille RCV000237295 SCV000583818 pathogenic Hypercholesterolemia, familial, 1 2017-03-30 criteria provided, single submitter clinical testing
Fundacion Hipercolesterolemia Familiar RCV000237295 SCV000607584 likely pathogenic Hypercholesterolemia, familial, 1 2016-03-01 criteria provided, single submitter research
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum RCV000237295 SCV000606388 pathogenic Hypercholesterolemia, familial, 1 no assertion criteria provided research

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