rs397509365

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PS1_ModeratePM1PM2PM5PP3_StrongPP5

The NM_000527.5(LDLR):c.1690A>C(p.Asn564His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000143 in 1,608,688 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 Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N564D) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

LDLR
NM_000527.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:17U:5

Conservation

PhyloP100: 9.21

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 13 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 strand (size 6) in uniprot entity LDLR_HUMAN there are 17 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 chr19-11116197-A-G is described in Lovd as [Pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.992

PP5

Variant 19-11116197-A-C is Pathogenic according to our data. Variant chr19-11116197-A-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 226365.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=6, Uncertain_significance=5, Pathogenic=7}. Variant chr19-11116197-A-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LDLR	NM_000527.5 link	c.1690A>C	p.Asn564His	missense_variant	Exon 11 of 18	ENST00000558518.6	NP_000518.1	P01130-1A0A024R7D5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LDLR	ENST00000558518.6 link	c.1690A>C	p.Asn564His	missense_variant	Exon 11 of 18	1	NM_000527.5	ENSP00000454071.1		P01130-1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152190

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000795

AC:

AN:

251416

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135902

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000137

AC:

AN:

1456498

Hom.:

Cov.:

AF XY:

0.0000166

AC XY:

AN XY:

725032

show subpopulations

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:

0.0000172

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152190

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74346

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:17Uncertain:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hypercholesterolemia, familial, 1

Pathogenic:13Uncertain:2

Mar 25, 2016

LDLR-LOVD, British Heart Foundation

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: literature only

- -

Aug 01, 2012

Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Aug 04, 2022

MGZ Medical Genetics Center

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 14, 2023

Revvity Omics, Revvity

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 01, 2016

Fundacion Hipercolesterolemia Familiar

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Mar 01, 2016

Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

0/208 non-FH alleles; 0/100 control subjects -

Dec 16, 2016

Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

subjects mutated among 2600 FH index cases screened = 8 , family member = 1 with co-segregation / systematically associated with c.2397_2405del, p.Val800_Leu802del & other mutations at same codon / Software predictions: Damaging -

Mar 01, 2016

Laboratory of Genetics and Molecular Cardiology, University of São Paulo

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Jan 27, 2019

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

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 01, 2016

Iberoamerican FH Network

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Dec 07, 2021

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

_x000D_The variant was found in the same patient as NM_000527.5:c.2397_2405delCGTCTTCCT. Criteria applied: PS3_MOD, PS4, PM2_SUP, PM5_STR, PP3, PP4 -

Robarts Research Institute, Western University

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 25, 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 histidine at codon 564 in the LDLR type B repeat 4 of the EGF precursor homology domain of the LDLR protein. Computational prediction tools indicate that this variant has a deleterious impact on protein structure and function. This variant has been reported to occur in cis with LDLR p.Val800_Leu802 variant in numerous individuals with hypercholesterolemia (PMID: 9143924, 9143924, 10090484, 12442279, 12442279, 15241806, 21475731, 24632281, 27784735, 27919364, 28475941, 30795984, 32143996, 33740630, 34387892). The double mutant allele is reported as a founder mutation associated with mild phenotype in the Dutch population (PMID: 21475731) and is also common among individuals of Spanish descent (PMID: 2463228). The double mutant allele has been shown to segregate with disease in multiple families (PMID: 9143924, 12442279). This p.Asn564His variant has been identified in 2/251416 chromosomes in the general population by the Genome Aggregation Database (gnomAD). One functional study showed that p.Asn564His or p.Val800_Leu802 variant, individually, did not alter LDLR function, while a mutant allele carrying both variants resulted in significantly reduced LDLR cell surface expression and function (PMID: 9143924), suggesting that the two variants may act in synergy to adversely affect LDLR function (PMID: 9143924). However, different missense variants occurring at codon 564 (p.Asn564Ser and p.Asn564Asp) are reported as disease-causing, indicating the functional and clinical importance of p.Asn564 residue (ClinVar variation ID: 224616, 251973). Based on the available evidence, we conclude that the hypercholesterolemia phenotype observed in individuals carrying the double mutant allele may be attributable to the p.Asn564His variant, while the role of p.Val800_Leu802 variant in disease remains unclear. Therefore, this p.Asn564His variant is classified as Likely Pathogenic. -

not provided

Pathogenic:3Uncertain:1

Aug 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

LDLR: PM1, PM2, PM5, PS4:Moderate, PS3:Supporting -

Jan 31, 2024

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PP1_strong, PP3, PM2_moderate, PM5, PS3_moderate, PS4 -

Clinical Genetics, Academic Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Oct 11, 2023

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Has been as reported as p.(N646H) or p.(N543H) (due to alternate nomenclature) in individuals with familial hypercholesterolemia (FH) (Jensen et al., 1997; Futema et al., 2012; Dron et al., 2020; Benedek et al., 2021; Leren et al., 2021; Castillo et al., 2022; Marco-Benedi et al., 2022; Sustar et al., 2022); Not observed at significant frequency in large population cohorts (gnomAD); Functional studies suggest p.(N564H) in cis with LDLR p.(V800_L802del) results in an affect on the enzyme function (Jensen et al., 1997; Castillo et al., 2002).; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 12442279, 18325082, 9147888, 22390909, 7550239, 10090484, 9259195, 15199436, 17765246, 21722902, 9143924, 27919364, 28475941, 30312929, 24987033, 26490271, 35913489, 34456049, 33955087, 33740630, 30293936, 32770674, 32719484, 27044878, 31447099, 10790219, 32041611, 23054246) -

Familial hypercholesterolemia

Pathogenic:1

Nov 21, 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 histidine, which is basic and polar, at codon 564 of the LDLR protein (p.Asn564His). This variant is present in population databases (rs397509365, gnomAD 0.002%). This variant has been observed in individuals affected with familial hypercholesterolemia (PMID: 7550239, 17765246, 23054246, 9147888, 9143924, 12442279, 10090484). This variant is frequently in cis with p.Val800_Leu802del and may represent a single allele. This variant is also known as N543H. ClinVar contains an entry for this variant (Variation ID: 226365). 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%. Experimental studies have shown that this variant has a mild impact on LDLR protein function. However, when expressed with p.Val800_Leu802del in the same cDNA, LDLR receptor function was greatly reduced (PMID: 9143924). 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: 18718593, 20145306, 20538126, 21376320). 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 specified

Uncertain:1

Jul 28, 2021

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: LDLR c.1690A>C (p.Asn564His) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251416 control chromosomes (i.e. 2 alleles in the European (non-Finnish) subpopulation) in the gnomAD database (v2.1 dataset). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. The variant, c.1690A>C (aka. N543H), has been reported in the literature in several individuals affected with Familial Hypercholesterolemia (e.g. Jensen_1996, Castillo_2002, Fouchier_2001, Umans-Eckenhausen_2002, Kusters_2011, Sjouke_2016, Martin-Campos_2018, Leren_2021), however in almost all of these cases the variant reportedly occurred together with c.2397_2405delCGTCTTCCT (p.Val800_Leu802del) on the same chromosome (i.e. in cis), as a complex allele. These reports therefore do not provide unequivocal conclusions about association of the variant in isolation with Familial Hypercholesterolemia. Publications also reported experimental evidence evaluating an impact on protein function, and demonstrated that when this variant was expressed in isolation, it had a mild effect on LDLR function (~75-85% activity of the normal; Jensen_1996), however, when it was part of the complex allele, i.e. occurring together with p.Val800_Leu802del in the same protein, the LDLR receptor function was markedly reduced (to ~20-25% of the normal; Jensen_1996, Castillo_2002). Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as VUS (n=2), likely pathogenic (n=2), or pathogenic (n=4). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Cardiovascular phenotype

Uncertain:1

Jul 01, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.N564H variant (also known as c.1690A>C), located in coding exon 11 of the LDLR gene, results from an A to C substitution at nucleotide position 1690. The asparagine at codon 564 is replaced by histidine, an amino acid with similar properties. This alteration, also described in the literature as p.N543H, has been reported in familial hypercholesterolemia (FH) cohorts and is often described on the same chromosome, or in cis, with another alteration, p.V800_L802del (Górski B et al. Hum Genet, 1998 May;102:562-5; Tricot-Guerber F et al. Hum Mutat, 1995;6:87-8; Lombardi P et al. Clin Genet, 1996 Dec;50:525-6; Day IN et al. Hum Mutat, 1997;10:116-27; Jensen HK et al. Atherosclerosis, 1999 Oct;146:337-44; Martín-Campos JM et al. J Clin Lipidol Sep;12:1452-1462). Functional studies suggest this alteration has a mild impact on function, though the impact may be greater when expressed with p.V800_L802del (Jensen HK et al. Hum Mutat, 1997;9:437-44). Another alteration at the same codon, p.N465S (c.1691A>G), has been described in association with FH (Górski B et al. Hum Genet, 1998 May;102:562-5. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence for this variant alone is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.47

BayesDel_addAF

Pathogenic

0.28

BayesDel_noAF

Pathogenic

0.18

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.91

D;.;.;.;.;.

Eigen

Pathogenic

0.78

Eigen_PC

Pathogenic

0.69

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.99

D;D;D;D;D;D

M_CAP

Pathogenic

0.81

MetaRNN

Pathogenic

0.99

D;D;D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.4

M;.;.;.;.;M

PrimateAI

Uncertain

0.51

PROVEAN

Pathogenic

-4.5

D;D;D;D;D;D

REVEL

Pathogenic

0.88

Sift

Uncertain

0.0010

D;D;D;D;D;D

Sift4G

Pathogenic

0.0010

D;D;D;D;D;D

Polyphen

1.0

D;.;.;.;.;.

Vest4

0.83

MutPred

0.94

Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);.;.;.;Gain of sheet (P = 0.0827);

MVP

1.0

MPC

0.82

ClinPred

0.98

GERP RS

5.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.92

gMVP

1.0

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