19-11129598-C-A

Variant names:

• chr19-11129598-C-A
• rs374045590
• NM_000527.5:c.2475C>A

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PS3 PS4 PP1_Strong PM2 PP3 PP4

This summary comes from the ClinGen Evidence Repository: The NM_000527.5 (LDLR):c.2475C>A (p.Asn825Lys) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying evidence codes (PM2, PP3, PS3, PP4, PS4, PP1_Strong) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012).The supporting evidence is as follows:PM2: PopMax MAF= 0.00001 in European (Non-Finnish) population (gnomAD v2.1.1).PP3: REVEL = 0.802.PS3: Level 1 experiment using heterologous cells (CHO), the experiments shown 50-60% LDL uptake, and normal LDL-LDLR binding (95%) and normal cell surface LDLR (95%), Etxebarria et al, 2015, Unidad de Biofísica (CSIC, UPV/EHU), Departamento de Bioquímica, Universidad del País Vasco, Spain, PMID25378237.PP4: Variant meets PM2 and is identified in >1 index cases who fulfil FH diagnostic criteria after alternative causes of high cholesterol were excluded.PS4: Variant meets PM2 and is identified in 22 unrelated index cases who fulfil FH diagnostic criteria. Four index cases from Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies (APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière), three of them had DLCN score ≥6, one met Simon Broome possible for FH. Three index cases with DLCN score ≥6, from Robarts Research Institute, Canada. One case fulfil criteria of TC and LDLc higher than the 95th percentile, with presence of tendon xanthomata, CAD in the proband or in a first degree relative, Chaves et al, 2001, Institute of cytological research and service of endocrinology and nutrition, University of Valencia, Spain, PMID 11600564. Fourteen index cases fulfil 2 of 3 criteria of: 1) TC>8mmol/l, LDL>6mmol/l, TG<2.5mmol/l, 2) CAD before 60yr or family history of CAD, 3) presence of tendon xanthoma, Brusgaard et al, 2006, Department of clinical biochemistry and clinical genetics, Odense University hospital, Denmark, PMID 16542394.PP1_Strong: Variant segregates with FH phenotype in 16 informative meiosis from more than 3 families. Two affected relatives, one each from 2 families tested positive for the variant from Robarts Research Institute, Canada. Fourteen affected relatives from unknown number of families tested positive for the variant, Brusgaard et al, 2006, Department of clinical biochemistry and clinical genetics, Odense University hospital, Denmark, PMID 16542394.PS1 not met: One other missense variant that leads to the same amino acid change at same codon, NM_000527.5 (LDLR):c.2475C>G (p.Asn825Lys), (ClinVarID 161265), is classified as Likely Pathogenic by these guidelines, therefore PS1 is not met. PM5 not met: One other missense variants in the same codon: NM_000527.5 (LDLR):c.2473A>G (p.Asn825Asp), (ClinVarID 252340) is classified as Likely Pathogenic by these guidelines, therefore PM5 not met. LINK:https://erepo.genome.network/evrepo/ui/classification/CA040801/MONDO:0007750/013

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: LDLR NM_000527.5 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:10
• Conservation: PhyloP100: -0.0920
• Publications: 12 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 16 ACMG points.

• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PP1: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: For more information check the summary or visit ClinGen Evidence Repository.
• PP4: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LDLR	NM_000527.5	c.2475C>A	p.Asn825Lys	missense_variant	Exon 17 of 18	ENST00000558518.6	NP_000518.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LDLR	ENST00000558518.6	c.2475C>A	p.Asn825Lys	missense_variant	Exon 17 of 18	1	NM_000527.5	ENSP00000454071.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251458 AF XY: 0.00000736

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461822 Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3 AN XY: 727208

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53408

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111960

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome Cov.: 31

Alfa AF: 0.0000726 Hom.: 0

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:10

Revision: reviewed by expert panel

Submissions by phenotype

Hypercholesterolemia, familial, 1 Pathogenic:5

Mar 01, 2016

Fundacion Hipercolesterolemia Familiar

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Mar 20, 2023

ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The NM_000527.5 (LDLR):c.2475C>A (p.Asn825Lys) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying evidence codes (PM2, PP3, PS3, PP4, PS4, PP1_Strong) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: PM2: PopMax MAF= 0.00001 in European (Non-Finnish) population (gnomAD v2.1.1). PP3: REVEL = 0.802. PS3: Level 1 experiment using heterologous cells (CHO), the experiments shown 50-60% LDL uptake, and normal LDL-LDLR binding (95%) and normal cell surface LDLR (95%), Etxebarria et al, 2015, Unidad de Biofísica (CSIC, UPV/EHU), Departamento de Bioquímica, Universidad del País Vasco, Spain, PMID25378237. PP4: Variant meets PM2 and is identified in >1 index cases who fulfil FH diagnostic criteria after alternative causes of high cholesterol were excluded. PS4: Variant meets PM2 and is identified in 22 unrelated index cases who fulfil FH diagnostic criteria. Four index cases from Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies (APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière), three of them had DLCN score >=6, one met Simon Broome possible for FH. Three index cases with DLCN score >=6, from Robarts Research Institute, Canada. One case fulfil criteria of TC and LDLc higher than the 95th percentile, with presence of tendon xanthomata, CAD in the proband or in a first degree relative, Chaves et al, 2001, Institute of cytological research and service of endocrinology and nutrition, University of Valencia, Spain, PMID 11600564. Fourteen index cases fulfil 2 of 3 criteria of: 1) TC>8mmol/l, LDL>6mmol/l, TG<2.5mmol/l, 2) CAD before 60yr or family history of CAD, 3) presence of tendon xanthoma, Brusgaard et al, 2006, Department of clinical biochemistry and clinical genetics, Odense University hospital, Denmark, PMID 16542394. PP1_Strong: Variant segregates with FH phenotype in 16 informative meiosis from more than 3 families. Two affected relatives, one each from 2 families tested positive for the variant from Robarts Research Institute, Canada. Fourteen affected relatives from unknown number of families tested positive for the variant, Brusgaard et al, 2006, Department of clinical biochemistry and clinical genetics, Odense University hospital, Denmark, PMID 16542394. PS1 not met: One other missense variant that leads to the same amino acid change at same codon, NM_000527.5 (LDLR):c.2475C>G (p.Asn825Lys), (ClinVarID 161265), is classified as Likely Pathogenic by these guidelines, therefore PS1 is not met. PM5 not met: One other missense variants in the same codon: NM_000527.5 (LDLR):c.2473A>G (p.Asn825Asp), (ClinVarID 252340) is classified as Likely Pathogenic by these guidelines, therefore PM5 not met. -

Mar 25, 2016

LDLR-LOVD, British Heart Foundation

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: literature only

- -

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

- -

-

Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Familial hypercholesterolemia Pathogenic:3

Mar 13, 2025

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 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 lysine, which is basic and polar, at codon 825 of the LDLR protein (p.Asn825Lys). This variant is present in population databases (rs374045590, gnomAD 0.0009%). This missense change has been observed in individuals with hypercholesterolemia (PMID: 11668640, 27830735, 36105085). This variant is also known as N804K. ClinVar contains an entry for this variant (Variation ID: 252341). 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%. Experimental studies have shown that this missense change affects LDLR function (PMID: 25378237). For these reasons, this variant has been classified as Pathogenic. -

Jan 10, 2025

GENinCode PLC

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The LDLR c.2475C>A p.(Asn825Lys) missense variant has been reported in >=10 FH patients meeting clinical criteria, including patients where alternative causes of high cholesterol were excluded (PS4_STRONG, PP4_SUPPORTING; PMIDs 15241806, 16542394, ClinGen FH VCEP data). This variant has been reported to segregate with FH in >=6 affected meioses (PP1_STRONG; PMID: 16542394, ClinGen FH VCEP data). This variant was detected in the homozygous state in a child with a homozygous FH phenotype, where phase has been confirmed by parental testing (PM3_MODERATE; PMID 10421221). The highest population minor allele frequency in gnomAD v2.1.1 is 0.000008792 in the European (non-Finnish) population, which is lower than the ClinGen FH VCEP threshold (=<0.0002) for PM2_MODERATE. This variant meets level 1 pathogenic functional study criteria with 50-60% LDL uptake in heterologous cells (CHO-ldlA7) (PS3_STRONG; PMID: 25378237). REVEL score is 0.802 (PP3_SUPPORTING). Based on the evidence listed above, we have classified this variant as Pathogenic. -

not provided Pathogenic:2

Mar 08, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate a damaging effect (PMID: 25378237); 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; This variant is associated with the following publications: (PMID: 30777337, 11668640, 33955087, 28323660, 29874871, 34575654, 34407635, 16424354, 15576851, 11600564, 27765764, 17426749, 35470684, 32770674, 15241806, 19318025, 16542394, 32041611, 21310417, 27578128, 25378237, 37719435) -

Jul 13, 2022

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.62
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.040
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.93	D;.;.;.;.
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Pathogenic	1.0	D;D;D;D;D
M_CAP	Pathogenic	0.76	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.2	M;.;.;.;M
PhyloP100		-0.092
PrimateAI	Uncertain	0.78	T
PROVEAN	Pathogenic	-5.6	D;D;D;D;D
REVEL	Pathogenic	0.80
Sift	Pathogenic	0.0	D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D
Polyphen		1.0	D;.;.;.;.
Vest4		0.71
MutPred		0.93		Gain of ubiquitination at N825 (P = 0.0138);.;.;.;Gain of ubiquitination at N825 (P = 0.0138);
MVP		1.0
MPC		0.87
ClinPred		0.99	D
GERP RS		2.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.94
gMVP		1.0
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: rs374045590; hg19: chr19-11240274;