ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.941-12G>A

dbSNP: rs879254734
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel RCV000237608 SCV002506350 likely pathogenic Hypercholesterolemia, familial, 1 2022-03-30 reviewed by expert panel curation The NM_000527.5 (LDLR): c.941-12G>A variant is classified as Likely Pathogenic evidence for Familial Hypercholesterolemia by applying evidence codes (PM2, PP4, PS4_Supporting, PP1) 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 Met: This variant is absent in gnomAD (gnomAD v2.1.1). PP4 Met: This variant meets PM2 and is identified in >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 4 unrelated index cases who fulfil DLCN criteria for FH diagnosis from 2 different labs: Three cases from Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies (APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière); one case from Robarts Research Institute, Canada. PP1 Met: Variant segregates with FH phenotype in 3 informative meiosis in one family (Institut National de la Santé et de la Recherche Médicale,and Université Paris Descartes, Paris, France, PMID: 20809525). PS3_Supporting: RNA assay using patient monocytes (level 3 functional assay) was reported from one research lab. Abnormal splicing of intron 6 was observed by gel electrophoresis only in patient cDNA but not in controls, using forward primer with 5' end located at c.864 (exon 6) and the reverse primer with 3' end at c.941-11. Sequencing confirmation on abnormal RT-PCR product was not performed and aberrant transcript was not quantified (Institut National de la Santé et de la Recherche Médicale,and Université Paris Descartes, Paris, France, PMID: 20809525).
LDLR-LOVD, British Heart Foundation RCV000237608 SCV000295088 likely pathogenic 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 RCV000237608 SCV000503265 pathogenic Hypercholesterolemia, familial, 1 2016-12-16 criteria provided, single submitter clinical testing subject mutated among 2600 FH index cases screened = 1
Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge RCV000237608 SCV000599353 likely pathogenic Hypercholesterolemia, familial, 1 2016-03-01 criteria provided, single submitter curation
Iberoamerican FH Network RCV000237608 SCV000748139 likely pathogenic Hypercholesterolemia, familial, 1 2016-03-01 criteria provided, single submitter research
Robarts Research Institute, Western University RCV000237608 SCV000782956 uncertain significance Hypercholesterolemia, familial, 1 2018-01-02 criteria provided, single submitter clinical testing
GeneDx RCV003325476 SCV004032043 likely pathogenic not provided 2023-03-02 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies suggest a damaging effect with abnormal splicing of intron 6 observed by gel electrophoresis (Marduel et al., 2010); This variant is associated with the following publications: (PMID: 20809525)
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum RCV000237608 SCV000606280 benign Hypercholesterolemia, familial, 1 no assertion criteria provided research

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