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

dbSNP: rs879254734

Total submissions: 9

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)
Ambry Genetics	RCV004992114	SCV005612296	likely pathogenic	Cardiovascular phenotype	2024-11-15	criteria provided, single submitter	clinical testing	The c.941-12G>A intronic variant results from a G to A substitution 12 nucleotides upstream from coding exon 7 in the LDLR gene. This variant was identified in one or more individuals with features consistent with familial hypercholesterolemia (FH) and segregated with disease in at least one family (Marduel M et al. Hum Mutat, 2010 Nov;31:E1811-24; Albuquerque J et al. Atherosclerosis, 2023 Oct;383:117314; Ambry internal data). In a RT-PCR assay, this variant showed a functionally abnormal splicing result (Marduel M et al. Hum Mutat, 2010 Nov;31:E1811-24). This nucleotide position is poorly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site and will result in the creation or strengthening of a novel splice acceptor site. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	RCV000237608	SCV000606280	benign	Hypercholesterolemia, familial, 1		no assertion criteria provided	research