rs875989904

chr19-11105556-ATGG-A

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1 PM2 PM4_Supporting PP5_Very_Strong

The NM_000527.5(LDLR):c.654_656del(p.Gly219del) variant causes a inframe deletion change. The variant allele was found at a frequency of 0.0000188 in 1,595,642 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★★). Synonymous variant affecting the same amino acid position (i.e. D217D) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000019 (0 hom.)
• Consequence: LDLR NM_000527.5 inframe_deletion
• Clinical Significance: Pathogenic reviewed by expert panel P:27
• Conservation: PhyloP100: 4.96

Genes affected

LDLR (HGNC:6547): (low density lipoprotein receptor) The low density lipoprotein receptor (LDLR) gene family consists of cell surface proteins involved in receptor-mediated endocytosis of specific ligands. The encoded protein is normally bound at the cell membrane, where it binds low density lipoprotein/cholesterol and is taken into the cell. Lysosomes release the cholesterol, which is made available for repression of microsomal enzyme 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase, the rate-limiting step in cholesterol synthesis. At the same time, a reciprocal stimulation of cholesterol ester synthesis takes place. Mutations in this gene cause the autosomal dominant disorder, familial hypercholesterolemia. Alternate splicing results in multiple transcript variants.[provided by RefSeq, May 2022]

ACMG classification

Verdict is Pathogenic. Variant got 13 ACMG points.

• PM1: In a hotspot region, there are 12 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 9 uncertain in NM_000527.5
• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_000527.5. Strenght limited to Supporting due to length of the change: 1aa.
• PP5: Variant 19-11105556-ATGG-A is Pathogenic according to our data. Variant chr19-11105556-ATGG-A is described in ClinVar as [Pathogenic]. Clinvar id is 226329.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr19-11105556-ATGG-A is described in Lovd as [Pathogenic]. Variant chr19-11105556-ATGG-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LDLR	NM_000527.5	c.654_656del	p.Gly219del	inframe_deletion	4/18	ENST00000558518.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LDLR	ENST00000558518.6	c.654_656del	p.Gly219del	inframe_deletion	4/18	1	NM_000527.5	P3

Frequencies

GnomAD3 genomes AF: 0.0000198 AC: 3 AN: 151336 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000289

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000211

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000279 AC: 7 AN: 250684 Hom.: 0 AF XY: 0.0000295 AC XY: 4 AN XY: 135736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000497

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000883

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.0000187 AC: 27 AN: 1444306 Hom.: 0 AF XY: 0.0000292 AC XY: 21 AN XY: 718064

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.000706

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000454

Gnomad4 OTH exome AF: 0.0000676

GnomAD4 genome AF: 0.0000198 AC: 3 AN: 151336 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 73924

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.000289

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000211

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000868 Hom.: 0

Bravo AF: 0.0000264

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:27

Revision: reviewed by expert panel

Submissions by phenotype

Hypercholesterolemia, familial, 1 Pathogenic:16

Likely pathogenic, criteria provided, single submitter	literature only	LDLR-LOVD, British Heart Foundation	Mar 25, 2016	- -
Likely pathogenic, 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	Dec 16, 2016	subjects mutated among 2600 FH index cases screened = 3 , family members = 3 with co-segregation / FH-Lithuania, < 5% LDLR Activity -
Pathogenic, criteria provided, single submitter	clinical testing	U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille	Mar 30, 2017	- -
Pathogenic, no assertion criteria provided	clinical testing	Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital	Feb 12, 2009	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Nov 14, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Dec 07, 2023	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. -
Pathogenic, criteria provided, single submitter	research	Iberoamerican FH Network	Mar 01, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	May 25, 2017	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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Robarts Research Institute, Western University	Jan 02, 2018	- -
Pathogenic, reviewed by expert panel	curation	ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	Jun 02, 2022	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. -
Pathogenic, criteria provided, single submitter	curation;literature only	Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge	Mar 01, 2016	- -
Likely pathogenic, criteria provided, single submitter	research	Brunham Lab, Centre for Heart and Lung Innovation, University of British Columbia	May 10, 2019	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation	Nov 05, 2016	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 1998	- -
Pathogenic, no assertion criteria provided	research	Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	New York Genome Center	Feb 23, 2022	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. -

not provided Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 16, 2021	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) -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2023	LDLR: PP1:Strong, PM2, PM4, PS3:Moderate, PP4, PS4:Supporting -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 18, 2021	PS4, PS3_moderate, PM4, PP4, PM3 -
Pathogenic, no assertion criteria provided	provider interpretation	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Jun 28, 2016	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). -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Sep 09, 2019	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. -

Familial hypercholesterolemia Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 18, 2024	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. -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 28, 2016	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Apr 17, 2023	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. -

Homozygous familial hypercholesterolemia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Oct 11, 2019

The p.Gly219del variant in LDLR (also known as FH Lithuania and G197del) has been reported in >75 families with hypercholesterolemia (Hobbs 1990, Meiner 1991, Gudnason 1993, Gorski 1998, Mandelshtam 1998, Heath 1999, Durst 2001, Kuhrova 2002, Taylor 2007, Junyent 2008, Chmara 2010, Tichy 2012, Hooper 2012, Sharifi 2016, Durst 2017, Smyth 2018). It is considered to be a founder mutation in the Ashkenazi Jewish population (Meiner 1991, Durst 2001). This variant has also been identified in 0.05% (5/10062) of Ashkenazi Jewish chromosomes by gnomAD (http://gnomad.broadinstitute.org) and has been reported in ClinVar (Variation ID 226329). This variant is a deletion of 1 amino acid at position 219 and is not predicted to alter the protein reading-frame. In vitro functional studies support an impact on protein function (Hobbs 1990). This variant meets the following ACMG/AMP Criteria: PS4, PM2, PM4_Supporting, PS3_Supporting. Based on these criteria, the variant would be classified as likely pathogenic but its recognized role as a founder mutation lends additional weight. In summary, the p.Gly219del is classified as pathogenic for autosomal dominant hypercholesterolemia. -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 15, 2021

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; Tichý 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. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs121908027; hg19: chr19-11216232;