Genetic Variant LDLR:p.Asn564Ser (chr19-11116198-A-G) – ACMG Classification: Pathogenic (17 pts)

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 17P and 0B. PM1PM5PP2PP3_StrongPP5_Very_Strong

The NM_000527.5(LDLR):c.1691A>G(p.Asn564Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000106 in 1,608,020 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. N564K) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000011 ( 0 hom. )

Consequence

LDLR
NM_000527.5 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:18

Conservation

PhyloP100: 9.21

Publications

16 publications found

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 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

LDLR links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

PM1

In a hotspot region, there are 18 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 9 uncertain in NM_000527.5

PM5

Other missense variant is known to change same aminoacid residue: Variant chr19-11116199-T-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 2160891.

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, 0.988

PP5

Variant 19-11116198-A-G is Pathogenic according to our data. Variant chr19-11116198-A-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 224616.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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
LDLR	NM_000527.5	MANE Select	c.1691A>G	p.Asn564Ser	missense	Exon 11 of 18	NP_000518.1
LDLR	NM_001195798.2		c.1691A>G	p.Asn564Ser	missense	Exon 11 of 18	NP_001182727.1
LDLR	NM_001195799.2		c.1568A>G	p.Asn523Ser	missense	Exon 10 of 17	NP_001182728.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
LDLR	ENST00000558518.6	TSL:1 MANE Select	c.1691A>G	p.Asn564Ser	missense	Exon 11 of 18	ENSP00000454071.1
LDLR	ENST00000252444.10	TSL:1	c.1949A>G	p.Asn650Ser	missense	Exon 11 of 18	ENSP00000252444.6
LDLR	ENST00000558013.5	TSL:1	c.1691A>G	p.Asn564Ser	missense	Exon 11 of 18	ENSP00000453346.1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152182

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

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:

0.0000278

AC:

AN:

251412

AF XY:

0.0000294

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000163

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000110

AC:

AN:

1455838

Hom.:

Cov.:

AF XY:

0.0000138

AC XY:

AN XY:

724716

show subpopulations

African (AFR)

AF:

0.0000300

AC:

AN:

33342

American (AMR)

AF:

0.0000447

AC:

AN:

44706

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26094

East Asian (EAS)

AF:

0.0000757

AC:

AN:

39654

South Asian (SAS)

AF:

0.0000580

AC:

AN:

86142

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53394

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5754

European-Non Finnish (NFE)

AF:

0.00000452

AC:

AN:

1106552

Other (OTH)

AF:

0.00

AC:

AN:

60200

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152182

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74342

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41452

American (AMR)

AF:

0.00

AC:

AN:

15262

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68034

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000209

Hom.:

Bravo

AF:

0.0000151

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:18

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hypercholesterolemia, familial, 1

Pathogenic:11

May 30, 2024

Revvity Omics, Revvity

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Feb 05, 2020

Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

Oct 18, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Aug 31, 2015

Cardiovascular Biomarker Research Laboratory, Mayo Clinic

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

MAF =<0.3%, likely pathogenic based on the integrative in-silico score, LDL-C >=160 mg/dL, previously reported as P/LP in the literature

May 23, 2019

Brunham Lab, Centre for Heart and Lung Innovation, University of British Columbia

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

Mar 25, 2016

LDLR-LOVD, British Heart Foundation

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:literature only

Juno Genomics, Hangzhou Juno Genomics, Inc

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Absent from controls (or at extremely low frequency if recessive) in Genome Aggregation Database, Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium.;Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc).;The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.;Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.

Mar 29, 2021

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.Asn564Ser variant in LDLR has been reported in at least 7 individuals with hypercholesterolemia, including 1 compound heterozygous occurrence in an individual with tendon xanthomas (Bertolini 2013 PMID: 23375686, Chiou 2010 PMID: 20538126, Chmara 2010 PMID: 20145306, Gorski 1998 PMID: 9654205, Leigh 2008 PMID: 18325082, Miyake 2009 PMID: 18718593, Vandrovcova 2013 PMID: 23680767). It has also been reported in 3 individuals with myocardial infarction (Safarova 2017 PMID: 28145427, Lee 2019 PMID: 30971288). This variant has been reported by other clinical laboratories in ClinVar (Variation ID 224616) and has also been identified in 0.0016% (3/18394) of East Asian chromosomes by gnomAD (http://gnomad.broadinstitute.org). Computational prediction tools and conservation analysis suggest that the p.Asn564Ser variant may impact the protein. Finally, multiple different changes at the same position (p.Asn564His, p.Asn564Asp) have been reported in individuals with familial hypercholesterolemia (FH); however, there is insufficient evidence to establish the pathogenicity of these variants. In summary, although additional studies are required to fully establish its clinical significance, the p.Asn564Ser variant meets criteria to be classified as likely pathogenic for autosomal dominant FH. ACMG/AMP Criteria applied: PS4_Moderate; PM2_Supporting, PM3, PP3.

Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:research

Jul 10, 2024

All of Us Research Program, National Institutes of Health

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This missense variant replaces asparagine with serine at codon 564 of the LDLR protein. This variant is also known as p.AAsn543Ser in the mature protein. This variant alters a conserved asparagine residue in the fourth LDLR type B repeat of the LDLR protein (a.a. 529-572), where pathogenic missense variants are found enriched (ClinVar-LDLR). Computational prediction tools indicate that this variant has a deleterious impact on protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in over fifteen individuals affected with familial hypercholesterolemia (PMID: 9654205, 18718593, 20145306, 20538126, 23375686, 25187945, 28145427, 28502495, 30592719, 31345425, 3399440, 35910211, 36329474; Color internal data) and in two individuals affected with myocardial infarction (PMID: 30637778). This variant has been identified in 7/251412 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Different variants affecting the same codon, p.Asn564His and p.Asn564Asp, are considered to be disease-causing (ClinVar variation ID: 3737, 251973), suggesting that asparagine at this position is important for LDLR protein function. Based on the available evidence, this variant is classified as Likely Pathogenic.

Mar 01, 2016

Fundacion Hipercolesterolemia Familiar

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

Familial hypercholesterolemia

Pathogenic:4

Mar 07, 2025

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

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: LDLR c.1691A>G (p.Asn564Ser) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.8e-05 in 251412 control chromosomes (gnomAD). c.1691A>G has been reported in the literature in individuals affected with Familial Hypercholesterolemia (e.g. Gorski_1998, Miyake_2008, Chiou_2010, Bertolini_2013, Lee_2019), including one case where it was found in the compound heterozygous state together with a splice variant (Bertolini_2013), and in at least two individuals who suffered a myocardial infarction (Lee_2019). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 23375686, 20538126, 9654205, 30971288, 18718593, 35339733). ClinVar contains an entry for this variant (Variation ID: 224616). Based on the evidence outlined above, the variant was classified as likely pathogenic.

Apr 04, 2024

Color Diagnostics, LLC DBA Color Health

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Sep 16, 2020

Natera, Inc.

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

Dec 18, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 564 of the LDLR protein (p.Asn564Ser). This variant is present in population databases (rs758194385, gnomAD 0.02%). This missense change has been observed in individuals with hypercholesterolemia (PMID: 9654205, 18718593, 20538126, 23375686). 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 N543S. ClinVar contains an entry for this variant (Variation ID: 224616). 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.Asn564 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16250003; internal data). 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.

not provided

Pathogenic:2

Jul 23, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The LDLR c.1691A>G (p.Asn564Ser) variant has been reported in the published literature in individuals with hypercholesterolemia (PMIDs: 9654205 (1998), 18718593 (2009), 20145306 (2010), 20538126 (2010), 23375686 (2013), 31345425 (2019), 32977124 (2020), 34182004 (2021), and 33994402 (2021)) and in individuals with myocardial infarction (PMIDs: 30637778 (2019) and 30971288 (2019)). A functional study has shown that this variant results in a reduced LDL-R activity (PMID: 23375686 (2013)). The frequency of this variant in the general population, 0.00016 (3/18394 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, this variant is classified as pathogenic.

Apr 04, 2023

GeneDx

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Also known as p.N543S; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25525159, 18325082, 34407635, 34428338, 20538126, 31447099, 34573395, 30637778, 32719484, 30971288, 33087929, 34515413, 28145427, 33740630, 34182004, 35339733, 35130036, 35910211, 9654205, 20145306, 31345425, 34037665, 25187945, 18718593, 33994402, 23375686, 30592719, 32977124)

Cardiovascular phenotype

Pathogenic:1

Feb 16, 2023

Ambry Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.N564S variant (also known as c.1691A>G), located in coding exon 11 of the LDLR gene, results from an A to G substitution at nucleotide position 1691. The asparagine at codon 564 is replaced by serine, an amino acid with highly similar properties. This variant has been detected in multiple individuals with familial hypercholesterolemia (FH) from a variety of ancestries (Górski B et al. Hum Genet, 1998 May;102:562-5; Miyake Y et al. Atherosclerosis, 2009 Mar;203:153-60; Lee C et al. Lipids Health Dis, 2019 Apr;18:95; Huang CC et al. J Atheroscler Thromb, 2021 May; [Epub ahead of print]; Sturm AC et al. JAMA Cardiol, 2021 08;6:902-909). This variant has also been reported in an individual with homozygous FH phenotype, who had a co-occurring LDLR splicing mutation (Bertolini S et al. Atherosclerosis, 2020 11;312:72-78). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). Based on the majority of available evidence to date, this variant is likely to be pathogenic.

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.033

BayesDel_noAF

Uncertain

-0.020

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.90

Eigen

Pathogenic

0.71

Eigen_PC

Uncertain

0.64

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.97

M_CAP

Pathogenic

0.75

MetaRNN

Pathogenic

0.99

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.1

PhyloP100

9.2

PrimateAI

Benign

0.44

PROVEAN

Uncertain

-4.2

REVEL

Pathogenic

0.77

Sift

Benign

0.039

Sift4G

Uncertain

0.051

Polyphen

1.0

Vest4

0.71

MutPred

0.93

Gain of sheet (P = 0.0827)

MVP

1.0

MPC

0.72

ClinPred

0.55

GERP RS

5.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.80

gMVP

1.0

Mutation Taster

=0/100

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over