ClinVar Miner

Submissions for variant NM_000527.4(LDLR):c.2140+1G>A (rs145787161)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
LDLR-LOVD, British Heart Foundation RCV000003942 SCV000295891 likely pathogenic Familial hypercholesterolemia 2016-03-25 criteria provided, single submitter literature only
Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge RCV000003942 SCV000323001 pathogenic Familial hypercholesterolemia 2016-03-01 criteria provided, single submitter research 0/200 non-FH alleles
Robarts Research Institute,Western University RCV000003942 SCV000484793 likely pathogenic Familial hypercholesterolemia criteria provided, single submitter clinical testing
Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies,APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix RCV000003942 SCV000503469 pathogenic Familial hypercholesterolemia 2016-12-16 criteria provided, single submitter clinical testing subject mutated among 2600 FH index cases screened = 1
Fundacion Hipercolesterolemia Familiar RCV000003942 SCV000607679 pathogenic Familial hypercholesterolemia 2016-03-01 criteria provided, single submitter research
Invitae RCV000775089 SCV000627027 pathogenic Familial hypercholesterolemias 2018-11-06 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 14 of the LDLR gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. Loss-of-function variants in LDLR are known to be pathogenic. This particular variant has been reported in individuals affected with familial hypercholesterolemia and to segregate with the disease in a large multigenerational family (PMID: 12522687, 15241806, 20828696, 23054246). Experimental studies have shown that this splice site variant leads to an aberrant splicing that results in the loss of the protein (PMID: 12522687). For these reasons, this variant has been classified as Pathogenic.
Color RCV000775089 SCV000909193 pathogenic Familial hypercholesterolemias 2018-10-03 criteria provided, single submitter clinical testing Pathogenic variant based on current evidence: This intronic variant is predicted to abolish the canonical splice donor site of intron 14 in the LDLR gene. An RNA study has shown that this variant causes an insertion of a 214-bp intronic sequence between exons 14 and 15 due to a cryptic splice donor activation, resulting in a frameshift and premature truncation (PMID: 12522687). Experimental functional studies have shown that this variant causes significant decrease in LDLR expression levels and LDL binding activity (PMID: 12522687). While this variant is rare in the general population (0/277264 chromosomes in the Genome Aggregation Database (gnomAD)), it has been identified in over 20 individuals affected with familial hypercholesterolemia (PMID: 12522687, 15241806, 20828696, 22883975, 23054246, 24627126, 27784735), including 14 individuals from a large pedigree (PMID: 12522687). Based on available evidence, this variant is classified as Pathogenic.
Illumina Clinical Services Laboratory,Illumina RCV000003942 SCV000914828 likely pathogenic Familial hypercholesterolemia 2018-11-13 criteria provided, single submitter clinical testing The LDLR c.2140+1G>A variant occurs in a canonical splice site (donor) and is therefore predicted to disrupt or distort the normal gene product. The c.2140+1G>A variant has been reported in at least three studies and is found in at least four probands with familial hypercholesterolemia in a heterozygous state (Mozas et al. 2004; Medeiros et al. 2010; Hooper et al. 2012). One of these patients also had a second splice site variant (Mozas et al. 2004). The c.2140+1G>A variant is reported at a frequency of 0.000116 in the European American population of the Exome Sequencing Project, but this is based on one allele in a region of good sequence coverage, so the variant is presumed to be rare. Due to the potential impact of splice donor variants, the c.2140+1G>A variant is classified as likely pathogenic for familial hypercholesterolemia. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
OMIM RCV000003942 SCV000024107 pathogenic Familial hypercholesterolemia 2004-01-01 no assertion criteria provided literature only
Cardiovascular Genetics Laboratory,PathWest Laboratory Medicine WA - Fiona Stanley Hospital RCV000003942 SCV000268658 pathogenic Familial hypercholesterolemia 2008-06-10 no assertion criteria provided clinical testing

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