rs879254597

chr19-11105528-G-Achr19-11105528-G-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PP3_Strong PP5_Very_Strong

The NM_000527.5(LDLR):c.622G>A(p.Glu208Lys) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,382 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 (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: LDLR NM_000527.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:13
• Conservation: PhyloP100: 5.49

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 16 ACMG points.

• PM1: In a hotspot region, there are 13 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 10 uncertain in NM_000527.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.972
• PP5: Variant 19-11105528-G-A is Pathogenic according to our data. Variant chr19-11105528-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 251328.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-11105528-G-A is described in Lovd as [Pathogenic]. Variant chr19-11105528-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LDLR	NM_000527.5	c.622G>A	p.Glu208Lys	missense_variant	4/18	ENST00000558518.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LDLR	ENST00000558518.6	c.622G>A	p.Glu208Lys	missense_variant	4/18	1	NM_000527.5	P3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461382 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 726996

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypercholesterolemia, familial, 1 Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Apr 28, 2023	This missense variant is located in the fifth LDLR type A repeat in the ligand binding domain of the LDLR protein. This variant is also known as p.Glu187Lys in the mature protein and as FH Jerusalem in the literature. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). A functional study using cells from a heterozygous individual have demonstrated a significantly reduced LDLR activity (PMID: 1301956). This variant has been reported in multiple unrelated individuals diagnosed with familial hypercholesterolemia (PMID: 1301956, 8882879, 9767373, 11810272, 22390909, 32759540, 32770674, 33418990, 34037665, 34363016). This variant has also been observed in homozygous state in individuals affected with homozygous familial hypercholesterolemia (PMID: 35249492). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on available evidence, this variant is classified as Pathogenic. -
Pathogenic, no assertion criteria provided	research	Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	-	- -
Likely pathogenic, criteria provided, single submitter	literature only	LDLR-LOVD, British Heart Foundation	Mar 25, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	Feb 04, 2020	This c.622G>A (p.Glu208Lys) variant in the LDLR gene has been reported in multiple individuals with familial hypercholesterolemia (PMID: 1301956, 9767373, 11810272, 22390909, 21722902). Functional studies have demonstrated a deleterious effect of the p.Glu208Lys variant on LDL binding (PMID: 1301956, 18677035). This variant is not present in the general population (gnomAD). Multiple algorithms predicted this change to be deleterious. Therefore, the c.622G>A (p.Glu208Lys) variant in the LDLR gene is classified as pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Jul 18, 2022	- -

not provided Pathogenic:3

Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Feb 18, 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; Published functional studies demonstrate that this variant, reported as E187K, has a damaging effect on LDL binding affinity (Hobbs et al., 1992; Zhao et al., 2008) and B-VLDL binding affinity (Zhao et al., 2008); Also known as p.E187K and FH-Jerusalem; This variant is associated with the following publications: (PMID: 22390909, 1301956, 11810272, 18677035, 9767373, 8882879, 2799589, 32770674, 33740630, 33418990, 34037665, 34363016, 32759540) -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Familial hypercholesterolemia Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 08, 2023	This missense variant is located in the fifth LDLR type A repeat in the ligand binding domain of the LDLR protein. This variant is also known as p.Glu187Lys in the mature protein and as FH Jerusalem in the literature. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). A functional study using cells from a heterozygous individual have demonstrated a significantly reduced LDLR activity (PMID: 1301956). This variant has been reported in multiple unrelated individuals diagnosed with familial hypercholesterolemia (PMID: 1301956, 8882879, 9767373, 11810272, 22390909, 32759540, 32770674, 33418990, 34037665, 34363016). This variant has also been observed in homozygous state in individuals affected with homozygous familial hypercholesterolemia (PMID: 35249492). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on available evidence, this variant is classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Apr 18, 2023	For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects LDLR function (PMID: 18677035). 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. ClinVar contains an entry for this variant (Variation ID: 251328). This variant is also known as p.Glu187Lys. This missense change has been observed in individuals with hypercholesterolaemia (PMID: 1301956, 22390909). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 208 of the LDLR protein (p.Glu208Lys). -

Homozygous familial hypercholesterolemia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 16, 2018

The p.Glu208Lys variant in LDLR (also described as p.Glu187Lys and FH Jerusalem in the literature) has been reported in >30 individuals with hypercholesterolemia, segregated with disease in 9 affected relatives from 3 families (Kotze 1989, Hobbs 1992, Ekstrom 1998, Fouchier 2001, Fouchier 2015), and was absent from large population studies. This variant has been reported in ClinVar (Variation ID: 251328). Functional studies provide some evidence that the p.Glu208Lys variant reduces protein activity (Hobbs 1992). Computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. In summary, this variant meets criteria to be classified as pathogenic for hypercholesterolemia in an autosomal dominant manner based upon segregation studies, absence from controls, and functional evidence. ACMG/AMP Criteria applied: PS4; PP1_Strong; PM2; PS3_Supporting. -

LDLR-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 24, 2023

The LDLR c.622G>A variant is predicted to result in the amino acid substitution p.Glu208Lys. This variant was reported in multiple individuals with familial hypercholesterolemia (reported as E187K in Table 2, Hobbs et al 1992. PubMed ID: 1301956; Table 1, Huijgen et al 2012. PubMed ID: 22390909; Table 4, Wang et al 2020. PubMed ID: 32759540; Table S5, Rieck et al 2020. PubMed ID: 32770674; Table A1, Meshkov et al 2021. PubMed ID: 33418990; Table S1, Leren TP et al 2021. PubMed ID: 33740630; e-Table 1, Sturm AC et al 2021. PubMed ID: 34037665). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic. -

Cardiovascular phenotype Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 30, 2017

The p.E208K variant (also known as c.622G>A), located in coding exon 4 of the LDLR gene, results from a G to A substitution at nucleotide position 622. The glutamic acid at codon 208 is replaced by lysine, an amino acid with similar properties, and is located in the ligand-binding domain. This alteration, also known as E187K, has been reported in multiple individuals with familial hypercholesterolemia (FH) from a variety of ethnic backgrounds, including an affected father-son pair; compound heterozygote cases with this alteration were also reported (Hobbs HH et al. Hum. Mutat., 1992;1:445-66; Reshef A et al. Hum. Genet., 1996 Nov;98:581-6; Fouchier SW et al. Hum. Genet., 2001 Dec;109:602-15; Huijgen R et al. Eur. Heart J., 2012 Sep;33:2325-30). One in vitro study demonstrated a ten-fold reduction in beta-VLDL binding with this alteration (Zhao Z et al. J. Biol. Chem., 2008 Sep;283:26528-37). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.54
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.42
Cadd	Pathogenic	28
Dann	Pathogenic	1.0
DEOGEN2	Uncertain	0.78	D;.;.;.
Eigen	Uncertain	0.38
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D;D;D;D
M_CAP	Pathogenic	0.44	D
MetaRNN	Pathogenic	0.97	D;D;D;D
MetaSVM	Pathogenic	0.94	D
MutationAssessor	Benign	1.2	L;.;.;L
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Uncertain	0.48	T
PROVEAN	Uncertain	-3.4	D;D;D;D
Sift	Benign	0.088	T;T;T;T
Sift4G	Uncertain	0.056	T;D;T;T
Polyphen		0.98	D;.;.;.
Vest4		0.79
MutPred		0.89		Gain of methylation at E208 (P = 0.0073);Gain of methylation at E208 (P = 0.0073);.;Gain of methylation at E208 (P = 0.0073);
MVP		1.0
MPC		0.54
ClinPred		0.97	D
GERP RS		5.6
Varity_R		0.76
gMVP		0.92

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs879254597; hg19: chr19-11216204;