ClinVar Miner

Submissions for variant NM_001195800.2(LDLR):c.314-1832_314-1830del (rs121908027)

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Total submissions: 17
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000589051 SCV000285032 pathogenic Familial hypercholesterolemia 2020-01-07 criteria provided, single submitter clinical testing This sequence change deletes 3 nucleotides from exon 4 of the LDLR mRNA (c.654_656delTGG). This leads to the deletion of 1 amino acid residue in the LDLR protein (p.Gly219del) but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs758036807, ExAC 0.008%). This variant is a known common cause of familial hypercholesterolemia in Ashkenazi Jewish population from Eastern Europe (PMID: 9744476, 11309683, 1867200), although it has been observed in individuals from other ethnicities (PMID: 17539906, 18096825, 22698793, 28104544). This variant is also known as p.G197del and p.Gly218del in the literature. Experimental studies and prediction algorithms are not available for this variant, and the functional significance of the deleted amino acid is currently unknown. For these reasons, this variant has been classified as Pathogenic.
LDLR-LOVD, British Heart Foundation RCV000211647 SCV000294853 likely pathogenic Familial hypercholesterolemia 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 RCV000211647 SCV000503197 likely pathogenic Familial hypercholesterolemia 1 2016-12-16 criteria provided, single submitter clinical testing subjects mutated among 2600 FH index cases screened = 3 , family members = 3 with co-segregation / FH-Lithuania, < 5% LDLR Activity
Molecular Genetics Laboratory,Centre for Cardiovascular Surgery and Transplantation RCV000211647 SCV000540747 likely pathogenic Familial hypercholesterolemia 1 2016-11-05 criteria provided, single submitter clinical testing
GeneDx RCV000489033 SCV000577590 pathogenic not provided 2018-09-19 criteria provided, single submitter clinical testing The c.654_656delTGG pathogenic variant in the LDLR gene, also reported historically as FH-Piscataway, FH- Lithuania, and G197del due to alternate nomenclature, has been reported previously in many individuals from various ethnic backgrounds with a diagnosis of FH (Hobbs et al., 1990; Gudnason et al., 1993; Giesel et al., 1995; Heath et al., 1999; Taylor et al., 2007; Junyent et al., 2008; Chmara et al., 2010; van der Graaf et al., 2011; Tichy et al., 2012; Hooper et al., 2012; Sharifi et al., 2016). Additionally, this variant is considered a Lithuanian Ashkenazi Jewish founder mutation (Meiner et al., 1991; Gorski et al., 1998; Durst et al., 2001; Durst et al., 2017). Furthermore, the c.654_656delTGG variant is not observed in large population cohorts (Lek et al., 2016). This variant results in the in-frame deletion of one amino acid, glycine 219, and does not result in a shift in reading frame or a premature stop codon. Nevertheless, functional studies show that the c.654_656delTGG variant results in slow processing and abnormal rate of transport to the Golgi complex likely due to protein mis-folding (Hobbs et al., 1990).
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille RCV000211647 SCV000583714 pathogenic Familial hypercholesterolemia 1 2017-03-30 criteria provided, single submitter clinical testing
Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge RCV000211647 SCV000599339 pathogenic Familial hypercholesterolemia 1 2016-03-01 criteria provided, single submitter curation
Integrated Genetics/Laboratory Corporation of America RCV000589051 SCV000697245 pathogenic Familial hypercholesterolemia 2016-03-28 criteria provided, single submitter clinical testing Variant Summary: The LDLR variant of interest causes an in-frame deletion resulting in the loss of a Glycine at codon 219. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 5/119648 (1/23930), which does not exceed the predicted maximum expected allele frequency for a pathogenic LDLR variant of 1/800. The variant of interest has been reported in multiple affected individuals via publications and has been indicated to be a founder mutation. Therefore, taking all available lines of evidence into consideration, the variant of interest is classified as Pathogenic.
Iberoamerican FH Network RCV000211647 SCV000748132 pathogenic Familial hypercholesterolemia 1 2016-03-01 criteria provided, single submitter research
Robarts Research Institute,Western University RCV000211647 SCV000782951 likely pathogenic Familial hypercholesterolemia 1 2018-01-02 criteria provided, single submitter clinical testing
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine RCV000211647 SCV000839990 pathogenic Familial hypercholesterolemia 1 2017-05-25 criteria provided, single submitter clinical testing The c.654_656del (p.Gly219del) variant in the LDLR gene has been detected in multiple cohorts of patients with hypercholesterolemia [PMID 22698793, 18096825, sometimes referred as G197del]. This variant is a founder mutation in the Ashkenazi Jewish population and traces its ancestry to Lithuania [PMID 1867200, 11309683, 9744476]. This variant leads to the deletion of one single amino acid and preserves the reading frame. This variant has been observed in only 5 individuals in the ExAC database ( This variant thus classified as pathogenic.
Color RCV000589051 SCV000909143 pathogenic Familial hypercholesterolemia 2017-05-16 criteria provided, single submitter clinical testing Pathogenic variant based on current evidence: This variant deletes 3 nucleotides from exon 4 of the LDLR gene, leading to the in-frame deletion of 1 amino acid from the fifth LDLR type A repeat of the ligand binding domain of the LDLR protein. This variant is also known as c.652_654 delGGT, p.G219del, p.Gly218del, p.G198del, p.G197del, FH-Piscataway, and FH-Lithuania in the literature. Experimental functional studies show that this variant causes defective protein transport to the Golgi complex (PMID: 2088165) and the mutant protein shows <2% LDLR activity in homozygote ( This variant is known to be a founder mutation in Lithuanian Ashkenazi Jewish population and is responsible for 35% of familial hypercholesterolemia cases observed in that population (PMID: 1867200, 11309683). This variant has also been reported in many affected individuals from other ethnicities (PMID: 10208479, 17539906, 18096825, 20145306, 22698793, 29369830). This variant is rare in the general population and has been identified in 7/245858 chromosomes by the Genome Aggregation Database (gnomAD). Based on available evidence, this variant is classified as Pathogenic.
Brunham Lab, Centre for Heart and Lung Innovation,University of British Columbia RCV000211647 SCV001432615 likely pathogenic Familial hypercholesterolemia 1 2019-05-10 criteria provided, single submitter research
OMIM RCV000211647 SCV000024037 pathogenic Familial hypercholesterolemia 1 1998-01-01 no assertion criteria provided literature only
Cardiovascular Genetics Laboratory,PathWest Laboratory Medicine WA - Fiona Stanley Hospital RCV000211647 SCV000268574 pathogenic Familial hypercholesterolemia 1 2009-02-12 no assertion criteria provided clinical testing
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde,Academisch Medisch Centrum RCV000211647 SCV000606180 pathogenic Familial hypercholesterolemia 1 no assertion criteria provided research
Stanford Center for Inherited Cardiovascular Disease, Stanford University RCV000489033 SCV000925137 pathogenic not provided 2016-06-28 no assertion criteria provided provider interpretation The patient had genetic testing for the familial hypercholesterolemia panel. The test included sequencing of three genes associated with familial hypercholesterolemia: LDLR, APOB and PCSK9. Results showed that the following variant was identified (see report below): C.654_656delTGG in the LDLR gene The lab classifies this variant as pathogenic. Given sufficient case data we consider this variant pathogenic and we do feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). The variant has been seen in many unrelated cases of FH (not including this patient's family). There is very strong case data and this variant appears to be a founder mutation originating within a Lithuanian Ashkenazi Jewish population which later immigrated to South Africa, Great Britain, Australia, North America and Israel. The prevalence of this variant is as high as 35.2% in a group of Ashkenazi-Israeli patients with FH. Functional studies of this variant show that it's a class II mutation that results in impaired intracellular transport and processing of the LDL receptor protein between the endoplasmic reticulum and Golgi complex (Hobbs, et al, 1990).

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