19-11105588-G-C

Variant names:

• chr19-11105588-G-C
• rs121908029
• NM_000527.5:c.682G>C

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 17P and 0B. PM1 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_000527.5(LDLR):​c.682G>C​(p.Glu228Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000809 in 1,606,936 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E228K) has been classified as Pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: LDLR NM_000527.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:16
• Conservation: PhyloP100: 9.88
• Publications: 67 publications found

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]

LDLR Gene-Disease associations (from GenCC):

• hypercholesterolemia, familial, 1

  Inheritance: AD, SD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, ClinGen
• homozygous familial hypercholesterolemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 17 ACMG points.

• PM1: In a hotspot region, there are 42 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 13 uncertain in NM_000527.5
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr19-11105588-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 3691.Status of the report is reviewed_by_expert_panel, 3 stars.
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 678 curated pathogenic missense variants (we use a threshold of 10). The gene has 92 curated benign missense variants. Gene score misZ: 0.12407 (below the threshold of 3.09). Trascript score misZ: 0.59338 (below the threshold of 3.09). GenCC associations: The gene is linked to hypercholesterolemia, familial, 1, homozygous familial hypercholesterolemia.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.95
• PP5: Variant 19-11105588-G-C is Pathogenic according to our data. Variant chr19-11105588-G-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 251393.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000527.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LDLR	NM_000527.5	MANE Select	c.682G>C	p.Glu228Gln	missense	Exon 4 of 18	NP_000518.1
	LDLR	NM_001195798.2		c.682G>C	p.Glu228Gln	missense	Exon 4 of 18	NP_001182727.1
	LDLR	NM_001195799.2		c.559G>C	p.Glu187Gln	missense	Exon 3 of 17	NP_001182728.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LDLR	ENST00000558518.6	TSL:1 MANE Select	c.682G>C	p.Glu228Gln	missense	Exon 4 of 18	ENSP00000454071.1
	LDLR	ENST00000252444.10	TSL:1	c.940G>C	p.Glu314Gln	missense	Exon 4 of 18	ENSP00000252444.6
	LDLR	ENST00000558013.5	TSL:1	c.682G>C	p.Glu228Gln	missense	Exon 4 of 18	ENSP00000453346.1

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 6 AN: 152184 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000161 AC: 4 AN: 247898 AF XY: 0.00000740

Gnomad AFR exome AF: 0.000196

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000481 AC: 7 AN: 1454752 Hom.: 0 Cov.: 34 AF XY: 0.00000415 AC XY: 3 AN XY: 722400

African (AFR) AF: 0.0000899 AC: 3 AN: 33356

American (AMR) AF: 0.00 AC: 0 AN: 44646

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26088

East Asian (EAS) AF: 0.00 AC: 0 AN: 39504

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86128

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52408

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5216

European-Non Finnish (NFE) AF: 0.00000181 AC: 2 AN: 1107414

Other (OTH) AF: 0.00 AC: 0 AN: 59992

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152184 Hom.: 0 Cov.: 33 AF XY: 0.0000404 AC XY: 3 AN XY: 74340

African (AFR) AF: 0.000121 AC: 5 AN: 41458

American (AMR) AF: 0.00 AC: 0 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10604

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68036

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000227

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:16

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypercholesterolemia, familial, 1 Pathogenic:8

Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

Mar 25, 2016

LDLR-LOVD, British Heart Foundation

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: literature only

Mar 30, 2023

Molecular Genetics, Royal Melbourne Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change in LDLR is predicted to replace glutamic acid with glutamine at codon 228, p.(Glu228Gln) (also known as FH Tulsa-2, FH Iraq, and p.Glu207Gln). The glutamic acid residue is highly conserved (100 vertebrates, UCSC), and is located in the LDL-receptor class A repeat 5 of the ligand-binding domain. Exon 4 (amino acids 105-232) where this variant is located, is defined as a mutational hotspot in LDLR. There is a small physicochemical difference between glutamic acid and glutamine. The highest population minor allele frequency in the population database gnomAD v3.1 is 0.01% (5/41,458 alleles) in the African/African American population, which is consistent with familial hypercholesterolaemia (FH). This is a recurrent variant that has been reported in multiple probands with FH and segregates with disease in at least one family (PMID: 25461735, 29720182, 32331935). This variant has been observed in trans with the variant c.663_683dup, p.(Asp221_Asp227dup) (PMID: 8599353) which is classified as pathogenic (ClinVar ID: 251358) in an individual with homozygous FH. Multiple lines of computational evidence predict a deleterious effect for the missense substitution (6/6 algorithms). Another missense variant c.682G>A, p.(Glu228Lys) in the same codon (with a similar physicochemical difference) has been classified as pathogenic for FH (ClinVar ID: 3691). Based on the classification scheme RMH Modified ACMG Guidelines v1.5.1, this variant is classified as PATHOGENIC. Following criteria are met: PM1, PM3, PM5, PS4_Supporting, PM2_Supporting, PP1, PP3.

Nov 05, 2016

Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Disrupt SDE motif. SDE bind structural Ca2+.

Nov 08, 2024

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is observed at an extremely low frequency in the gnomAD v4.1.0 dataset (total allele frequency: <0.001%). Predicted Consequence/Location: The variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported. In silico tool predictions suggest damaging effect of the variant on gene or gene product [REVEL: 0.94 (>=0.6, sensitivity 0.68 and specificity 0.92); 3Cnet: 1.00 (>=0.6, sensitivity 0.72 and precision 0.9)]. The same nucleotide change resulting in the same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000251393 /PMID: 1301956). Different missense changes at the same codon (p.Glu228Ala, p.Glu228Asp, p.Glu228Gly, p.Glu228Lys) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000003691, VCV000251394, VCV000375796, VCV000523724, VCV000689346 /PMID: 15497035, 2318961, 28502510, 31106925, 31491741). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.

Mar 01, 2016

Laboratory of Genetics and Molecular Cardiology, University of São Paulo

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

Mar 30, 2017

U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Aug 02, 2022

Institute of Immunology and Genetics Kaiserslautern

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACMG Criteria: PS3, PS4, PM2_P, PM5, PP3, PP4, PP5; Variant was found in heterozygous state.

Familial hypercholesterolemia Pathogenic:4

Dec 31, 2019

Color Diagnostics, LLC DBA Color Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant (also known as p.Glu207Gln in the mature protein and as FH Tulsa-2) replaces glutamic acid with glutamine at codon 228 in the LDLR type A repeat 5 of the LDLR protein. The LDLR type A repeat 5 forms a Ca2+ binding pocket that is important for proper LDLR protein folding. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. This variant has been reported in heterozygosity in multiple individuals affected with familial hypercholesterolemia (PMID: 8882879, 12205127, 15199436, 16250003, 16389549, 17094996). This variant has also been reported in a child affected with severe hypercholesterolemia and cutaneous xanthomata, who was compound heterozygous for this variant and another pathogenic variant (PMID: 1301956, 8599353). LDLR activity was <5% in the cells obtained from this individual compound heterozygous individual (PMID: 1301956, 8599353). This variant has been identified in 4/247898 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different missense variant at the same position, p.Glu228Lys, is pathogenic (Clinvar variation ID: 3691), indicating that glutamic acid at this position is important for LDLR function. Based on the available evidence, this variant is classified as Pathogenic.

Oct 12, 2017

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The LDLR c.682G>C (p.Glu228Gln) variant involves the alteration of a conserved nucleotide. 4/5 in silico tools predict a damaging outcome for this variant. This variant was found in 4/244590 control chromosomes at a frequency of 0.0000164, which does not exceed the estimated maximal expected allele frequency of a pathogenic LDLR variant (0.0012508). The variant has been reported in numerous affected individuals in the literature and has been reported twice was observed in patients with <5% LDLR activity who carried a second LDLR variant (Hobbs_1992, Blackett_1995). Other variants at the same residue (p.E228K, p.E228A and p.E228*) have also been reported in the literature and databases in association with hypercholesterolaemia, suggesting the residue p.Glu228 could represent mutation hot-spot. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as likely pathogenic/pathogenic. Taken together, this variant is classified as pathogenic.

Dec 25, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glutamic acid, which is acidic and polar, with glutamine, which is neutral and polar, at codon 228 of the LDLR protein (p.Glu228Gln). This variant is present in population databases (rs121908029, gnomAD 0.02%). This missense change has been observed in individual(s) with heterozygous familial hypercholesterolemia (PMID: 1301956, 8882879, 16250003, 17094996). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. Invitae Evidence Modeling of clinical and family history, age, sex, and reported ancestry of multiple individuals with this LDLR variant has been performed. This variant is expected to be pathogenic with a positive predictive value of at least 99%. This is a validated machine learning model that incorporates the clinical features of 363,995 individuals referred to our laboratory for LDLR testing. This variant is also known as p.Glu207Gln. ClinVar contains an entry for this variant (Variation ID: 251393). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt LDLR protein function with a positive predictive value of 95%. This variant disrupts the p.Glu228 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 1301956, 15359125, 18677035, 20736250). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

Jul 07, 2021

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

not provided Pathogenic:3

Jun 17, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as FH Tulsa-2/Iraq and E207Q; This variant is associated with the following publications: (PMID: 15199436, 16389549, 31401775, 31491741, 32331935, 1301956, 24507775, 8882879, 17094996, 16250003, 31447099, 33740630, 34037665, 29720182, 8599353)

Oct 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

LDLR: PS4, PM1, PM5, PP1, PS3:Supporting

Apr 27, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The LDLR c.682G>C (p.Glu228Gln) variant (also known as FH Tulsa-2 and E207Q) has been reported in the published literature in multiple individuals/families affected with hypercholesterolemia (PMIDs: 34037665 (2021), 32331935 (2020), 29720182 (2018), 25461735 (2015), 24507775 (2014), 17094996 (2007), 16389549 (2006), 16250003 (2005), 15199436 (2004), 8882879 (1996)). Experimental evidence indicates that this variant has a deleterious effect on LDLR protein function (PMIDs: 8784348 (1996), 1301956 (1992)). The frequency of this variant in the general population, 0.000196 (3/15314 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Based on the available information, this variant is classified as pathogenic.

Cardiovascular phenotype Pathogenic:1

Nov 16, 2021

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.E228Q pathogenic mutation (also known as c.682G>C), located in coding exon 4 of the LDLR gene, results from a G to C substitution at nucleotide position 682. The glutamic acid at codon 228 is replaced by glutamine, an amino acid with highly similar properties, and is located in an SDE motif in the ligand binding domain. This alteration, historically described as p.E207Q, FH Tulsa-2, and FH Iraq, has been detected in numerous individuals with familial hypercholesterolemia (FH) across multiple ethnicities, with segregation reported in at least one first degree family member; at least two homozygous FH (HoFH) cases have been reported, both of whom had an additional LDLR variant detected (Hobbs HH et al. Hum. Mutat., 1992;1:445-66; Blackett PR et al. Am J Med Genet, 1995 Nov;59:300-3; Reshef A et al. Hum. Genet., 1996 Nov;98:581-6; Fouchier SW et al. Hum. Mutat., 2005 Dec;26:550-6; Jannes CE et al. Atherosclerosis, 2015 Jan;238:101-7; Paththinige CS et al. Lipids Health Dis, 2018 May;17:100; Tada H et al. J Clin Lipidol May-June 2020;14:346-351.e9). In addition, limited functional studies have suggested a reduction of LDLR activity to approximately 2-5% of wild-type (Hobbs HH et al. Hum. Mutat., 1992;1:445-66). In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.58
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.95	D
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.92
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Pathogenic	0.91	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.1	H
PhyloP100		9.9
PrimateAI	Benign	0.46	T
PROVEAN	Uncertain	-2.8	D
REVEL	Pathogenic	0.94
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.77
MVP		1.0
MPC		0.80
ClinPred		0.99	D
GERP RS		5.6
PromoterAI		-0.045	Neutral
Varity_R		0.99
gMVP		0.99
Mutation Taster		=0/100	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs121908029; hg19: chr19-11216264;