19-11105588-G-C

Position:

chr19-11105588-G-C

Variant summary

Our verdict is Pathogenic. Variant got 20 ACMG points: 20P and 0B. PS1_ModeratePM1PM2PM5PP3_StrongPP5_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 nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E228K) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

LDLR
NM_000527.5 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:14

Conservation

PhyloP100: 9.88

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 20 ACMG points.

PS1

Transcript NM_000527.5 (LDLR) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt

PM1

In a helix (size 2) in uniprot entity LDLR_HUMAN there are 16 pathogenic changes around while only 0 benign (100%) in NM_000527.5

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.

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 [Likely_pathogenic]. Clinvar id is 251393.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-11105588-G-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LDLR	NM_000527.5 linkuse as main transcript	c.682G>C	p.Glu228Gln	missense_variant	4/18	ENST00000558518.6	NP_000518.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LDLR	ENST00000558518.6 linkuse as main transcript	c.682G>C	p.Glu228Gln	missense_variant	4/18	1	NM_000527.5	ENSP00000454071	P3	P01130-1

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152184

Hom.:

Cov.:

show subpopulations

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

GnomAD3 exomes

AF:

0.0000161

AC:

AN:

247898

Hom.:

AF XY:

0.00000740

AC XY:

AN XY:

135086

show subpopulations

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 SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000481

AC:

AN:

1454752

Hom.:

Cov.:

AF XY:

0.00000415

AC XY:

AN XY:

722400

show subpopulations

Gnomad4 AFR exome

AF:

0.0000899

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000181

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152184

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74340

show subpopulations

Gnomad4 AFR

AF:

0.000121

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000227

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:14

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hypercholesterolemia, familial, 1

Pathogenic:6

Likely pathogenic, criteria provided, single submitter	clinical testing	Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation	Nov 05, 2016	Disrupt SDE motif. SDE bind structural Ca2+. -
Likely pathogenic, criteria provided, single submitter	literature only	LDLR-LOVD, British Heart Foundation	Mar 25, 2016	- -
Likely pathogenic, criteria provided, single submitter	research	Laboratory of Genetics and Molecular Cardiology, University of São Paulo	Mar 01, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille	Mar 30, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Molecular Genetics, Royal Melbourne Hospital	Mar 30, 2023	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. -
Pathogenic, no assertion criteria provided	research	Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	-	- -

Familial hypercholesterolemia

Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 09, 2023	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. This variant is also known as p.Glu207Gln. ClinVar contains an entry for this variant (Variation ID: 251393). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Dec 31, 2019	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. -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Jul 07, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 12, 2017	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. -

not provided

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Oct 10, 2018	The best available variant frequency is uninformative. Statistically enriched in patients compared to ethnically matched controls. Predicted to have a damaging effect on the protein. Assessment of experimental evidence suggests this variant results in abnormal protein function. -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2023	LDLR: PS4, PM1, PM5, PP1, PS3:Supporting -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 17, 2022	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) -

Cardiovascular phenotype

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 16, 2021

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 v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.93

BayesDel_addAF

Pathogenic

0.38

BayesDel_noAF

Pathogenic

0.58

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.95

D;.;.;.

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

0.92

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Pathogenic

1.0

D;D;D;D

M_CAP

Pathogenic

0.91

MetaRNN

Pathogenic

0.95

D;D;D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

4.1

H;.;.;H

MutationTaster

Benign

1.0

D;D;D;D;D;D;D

PrimateAI

Benign

0.46

PROVEAN

Uncertain

-2.8

D;D;D;D

REVEL

Pathogenic

0.94

Sift

Uncertain

0.0010

D;D;D;D

Sift4G

Uncertain

0.0030

D;D;D;D

Polyphen

1.0

D;.;.;.

Vest4

0.77

MVP

1.0

MPC

0.80

ClinPred

0.99

GERP RS

5.6

Varity_R

0.99

gMVP

0.99

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over