ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.651TGG[1] (p.Gly219del)

dbSNP: rs121908027
Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 25
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel RCV000211647 SCV002568106 pathogenic Hypercholesterolemia, familial, 1 2022-06-02 reviewed by expert panel curation NM_000527.5(LDLR):c.651TGG[1] (p.Gly219del) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying evidence codes (PP1_strong, PS3_moderate, PS4, PM2, PM4 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: PP1_strong - Variant segregates with phenotype in 9 informative meiosis in 5 families from different labs (Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies (APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière); Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation); Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA)): 9 affected family members have the variant. PS3_moderate - PMID: 2088165 - Level 2 assay - Homozygous patients' fibroblasts, 125I-LDL assays: <2% LDLR activity. PS4 - Variant meets PM2. Variant identified in 10 unrelated index cases (1 case with DLCN ≥ 6 from Robarts Research Institute; 2 cases with DLCN ≥ 6 from Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies (APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière); 4 cases with Simon Broome possible/definite FH from Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation); 1 case with DLCN ≥ 6 from Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA); 2 cases with Simon Broome possible/definite FH from GeneDx Inc. PM2 - PopMax MAF = 0.000008826 (0.0008826%) in European (non-Finnish) exomes+genomes (gnomAD v2.1.1). PM4 - Variant meets PM2 and is in frame deletion. PP4 - Variant meets PM2. Identified in 4 FH case from Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation) with clinical Simon Broome possible/definite FH, after alternative causes of high cholesterol were excluded.
Invitae RCV000589051 SCV000285032 pathogenic Familial hypercholesterolemia 2024-01-18 criteria provided, single submitter clinical testing This variant, c.654_656del, results in the deletion of 1 amino acid(s) of the LDLR protein (p.Gly219del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs758036807, gnomAD 0.05%). This variant has been observed in individuals with familial hypercholesterolemia (PMID: 1867200, 9744476, 11309683). It is commonly reported in individuals of Ashkenazi Jewish ancestry (PMID: 1867200, 9744476, 11309683, 17539906, 18096825, 22698793, 28104544). This variant is also known as p.G197del and p.Gly218del. ClinVar contains an entry for this variant (Variation ID: 226329). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. For these reasons, this variant has been classified as Pathogenic.
LDLR-LOVD, British Heart Foundation RCV000211647 SCV000294853 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 RCV000211647 SCV000503197 likely pathogenic Hypercholesterolemia, familial, 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 Hypercholesterolemia, familial, 1 2016-11-05 criteria provided, single submitter clinical testing
GeneDx RCV000489033 SCV000577590 pathogenic not provided 2021-11-16 criteria provided, single submitter clinical testing Reported historically as FH-Piscataway, FH- Lithuania, and G197del due to alternate nomenclature, and considered a Lithuanian Ashkenazi Jewish founder mutation (Meiner et al., 1991; Gorski et al., 1998; Durst et al., 2001; Durst et al., 2017); In-frame deletion of 1 amino acid in a non-repeat region; Published functional studies demonstrate a damaging effect with slow processing and abnormal rate of transport to the Golgi complex likely due to protein misfolding (Hobbs et al., 1990); Reported as pathogenic/likely pathogenic by other clinical laboratories in ClinVar (ClinVar Variant ID#226329; ClinVar); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 7649546, 2088165, 24075752, 29369830, 31447099, 10208479, 1867200, 8093663, 26892515, 11309683, 9654205, 17539906, 18096825, 22698793, 28104544, 21382890, 22883975, 20145306, 27824480, 7682459, 9744476, 32143996, 32220565, 31153847, 33418990, 34037665)
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille RCV000211647 SCV000583714 pathogenic Hypercholesterolemia, familial, 1 2017-03-30 criteria provided, single submitter clinical testing
Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge RCV000211647 SCV000599339 pathogenic Hypercholesterolemia, familial, 1 2016-03-01 criteria provided, single submitter curation
Women's Health and Genetics/Laboratory Corporation of America, LabCorp 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 Hypercholesterolemia, familial, 1 2016-03-01 criteria provided, single submitter research
Robarts Research Institute, Western University RCV000211647 SCV000782951 likely pathogenic Hypercholesterolemia, familial, 1 2018-01-02 criteria provided, single submitter clinical testing
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine RCV000211647 SCV000839990 pathogenic Hypercholesterolemia, familial, 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 (http://exac.broadinstitute.org/variant/19-11216232-ATGG-A). This variant thus classified as pathogenic.
Color Diagnostics, LLC DBA Color Health RCV000589051 SCV000909143 pathogenic Familial hypercholesterolemia 2023-04-17 criteria provided, single submitter clinical testing 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. Functional studies have shown that this variant causes defective protein transport to the Golgi complex (PMID: 2088165) and the mutant protein shows <2% LDLR activity in cells from a homozygous individual (http://www.ucl.ac.uk/ldlr/). This variant is known to be a founder mutation in the Lithuanian Ashkenazi Jewish population and has been observed in 35% of 71 Ashkenazi Jewish families affected with familial hypercholesterolemia (PMID: 1867200, 11309683). This variant has also been reported in over 40 additional individuals affected with familial hypercholesterolemia (PMID: 10208479, 17539906, 18096825, 22698793, 29369830, 31345425, 32220565, 33418990, 34037665, 35052492; Color internal data). This variant has been identified in 7/250684 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.
Brunham Lab, Centre for Heart and Lung Innovation, University of British Columbia RCV000211647 SCV001432615 likely pathogenic Hypercholesterolemia, familial, 1 2019-05-10 criteria provided, single submitter research
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000489033 SCV001469534 pathogenic not provided 2019-09-09 criteria provided, single submitter clinical testing The best available variant frequency is uninformative because it is below the disease allele frequency. This variant is statistically more frequent in affected individuals than in the general population and/or healthy controls. Assessment of experimental evidence suggests this variant results in abnormal protein function.
Mayo Clinic Laboratories, Mayo Clinic RCV000489033 SCV001715240 pathogenic not provided 2021-02-18 criteria provided, single submitter clinical testing PS4, PS3_moderate, PM4, PP4, PM3
Ambry Genetics RCV002363056 SCV002658972 pathogenic Cardiovascular phenotype 2021-04-15 criteria provided, single submitter clinical testing The c.654_656delTGG pathogenic mutation (also known as p.G219del) is located in coding exon 4 of the LDLR gene. This pathogenic mutation results from an in-frame TGG deletion at nucleotide positions 654 to 656. This results in the in-frame deletion of a glycine at codon 219. This mutation (also described as legacy p.G197del, FH-Lithuania, FH-Piscataway) has been reported in numerous familial hypercholesterolemia cohorts, and co-segregation with disease has been reported in at least one family (Hobbs HH et al, Annu. Rev. Genet. 1990; 24:133-70; Mandelshtam M et al. Hum Mutat, 1998;12:255-8; Tich&yacute; L et al. Atherosclerosis, 2012 Aug;223:401-8; Meshkov A et al. Genes (Basel), 2021 Jan;12:[Epub ahead of print]). Fibroblast studies from a homozygous individual with this mutation were found to have very low residual LDLR activity, and functional studies results showed impaired intracellular transport and processing of the LDL receptor protein between the endoplasmic reticulum and Golgi complex (Hobbs HH et al, Annu. Rev. Genet. 1990; 24:133-70; Hobbs HH et al. Hum Mutat, 1992;1:445-66). Haplotype analysis demonstrated shared lineage demonstrating a founder effect, originating within a Lithuanian Ashkenazi Jewish population (Meiner V et al. Am J Hum Genet. 1991;49(2):443-449; Durst R et al. Am J Hum Genet, 2001 May;68:1172-88). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
New York Genome Center RCV000211647 SCV002764421 pathogenic Hypercholesterolemia, familial, 1 2022-02-23 criteria provided, single submitter clinical testing The c.654_656del (p.Gly219del) variant identified in the LDLR gene is a single amino acid, in-frame deletion of residue 219 of 861 (exon 4/18). This variant has also been historically called p.Gly197del, FH-Piscataway, or FH-Lithuania, and is thought to be a founder allele in some Lithuanian populations [PMID:11309683], although it is observed pan-ethnically. This variant is found with low frequency in gnomAD(v3.0) (3 heterozygotes, 0 homozygotes; allele frequency:1.98e-5) suggesting it is not a common benign variant in the populations represented in that database. This variant is reported in ClinVar as Pathogenic/LikelyPathogenic (VarID:226329), and has been reported in many affected individuals in the literature [PMID:31345425, 28104544, 22698793, others]. Functional studies demonstrate significantly reduced LDLR activity [PMID:2088165]. Given its presence in many affected individuals in the literature, low frequency in population databases, and functional studies showing reduced activity, the c.654_656del (p.Gly219del) variant identified in the LDLR gene is reported as Pathogenic.
Revvity Omics, Revvity Omics RCV000211647 SCV003825366 pathogenic Hypercholesterolemia, familial, 1 2022-11-14 criteria provided, single submitter clinical testing
CeGaT Center for Human Genetics Tuebingen RCV000489033 SCV004033639 pathogenic not provided 2023-07-01 criteria provided, single submitter clinical testing LDLR: PP1:Strong, PM2, PM4, PS3:Moderate, PP4, PS4:Supporting
OMIM RCV000211647 SCV000024037 pathogenic Hypercholesterolemia, familial, 1 1998-01-01 no assertion criteria provided literature only
Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital RCV000211647 SCV000268574 pathogenic Hypercholesterolemia, familial, 1 2009-02-12 no assertion criteria provided clinical testing
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum RCV000211647 SCV000606180 pathogenic Hypercholesterolemia, familial, 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).
Natera, Inc. RCV000589051 SCV001456146 pathogenic Familial hypercholesterolemia 2020-09-16 no assertion criteria provided clinical testing

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.