19-11129598-C-G

Position:

chr19-11129598-C-G

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PS1PM2PP3PP4PS4_Supporting

This summary comes from the ClinGen Evidence Repository: The NM_000527.5 (LDLR):c.2475C>G (p.Asn825Lys) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying evidence codes (PM2, PP3, PS1, PP4, PS4_Supporting) 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 = 0.00002 in European (Non-Finnish) in gnomAD (gnomAD v2.1.1).PP3: REVEL = 0.803.PS1: One other missense variant that leads to the same amino acid change at same codon, NM_000527.5 (LDLR):c.2475C>A (p.Asn825Lys), (ClinVarID 252341), is classified as Pathogenic by these guidelines.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_Supporting: Variant meets PM2 and is identified in 5 index cases who fulfil FH diagnostic criteria. Four index cases met DLCN criteria for definite or probable FH: 1 case from Department of Medicine and Cardiology, Aarhus Amtssygehus University Hospital, Denmark, PMID 10532689; 1 case from Department of Vascular Medicine, Academic Medical Center at the University of Amsterdam, The Netherlands, PMID 11810272; 1 case from Robarts Research Institute, Canada, PMID 11668627; 1 case submitted to ClinVar from U4M - Lille University & CHRU Lille, France. One proband with LDLC >10mmol/l and xanthoma, reported by Jiang et al, 2016, Department of atherosclerosis, Capital Medical University, China, PMID 27830735. LINK:https://erepo.genome.network/evrepo/ui/classification/CA023675/MONDO:0007750/013

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

LDLR
NM_000527.5 missense

Scores

12

6

1

Clinical Significance

Likely pathogenic reviewed by expert panel P:11

Conservation

PhyloP100: -0.0920

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:

LDLR (HGNC:):

LDLR links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

PS1

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.

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/exons	MANE	Protein	UniProt
LDLR	NM_000527.5 linkuse as main transcript	c.2475C>G	p.Asn825Lys	missense_variant	17/18	ENST00000558518.6	NP_000518.1	P01130-1A0A024R7D5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LDLR	ENST00000558518.6 linkuse as main transcript	c.2475C>G	p.Asn825Lys	missense_variant	17/18	1	NM_000527.5	ENSP00000454071.1		P01130-1

Frequencies

GnomAD3 genomes

Cov.:

31

GnomAD3 exomes

AF:

0.00000795

AC:

2

AN:

251458

Hom.:

0

AF XY:

0.00

AC XY:

0

AN XY:

135912

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:

6.84e-7

AC:

1

AN:

1461822

Hom.:

0

Cov.:

32

AF XY:

0.00000138

AC XY:

1

AN XY:

727208

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

31

ESP6500AA

AF:

0.00

AC:

0

ESP6500EA

AF:

0.000233

AC:

2

ExAC

AF:

0.0000165

AC:

2

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:11

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Hypercholesterolemia, familial, 1

Pathogenic:7

Likely pathogenic, reviewed by expert panel	curation	ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	Mar 20, 2023	The NM_000527.5 (LDLR):c.2475C>G (p.Asn825Lys) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying evidence codes (PM2, PP3, PS1, PP4, PS4_Supporting) 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 = 0.00002 in European (Non-Finnish) in gnomAD (gnomAD v2.1.1). PP3: REVEL = 0.803. PS1: One other missense variant that leads to the same amino acid change at same codon, NM_000527.5 (LDLR):c.2475C>A (p.Asn825Lys), (ClinVarID 252341), is classified as Pathogenic by these guidelines. 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_Supporting: Variant meets PM2 and is identified in 5 index cases who fulfil FH diagnostic criteria. Four index cases met DLCN criteria for definite or probable FH: 1 case from Department of Medicine and Cardiology, Aarhus Amtssygehus University Hospital, Denmark, PMID 10532689; 1 case from Department of Vascular Medicine, Academic Medical Center at the University of Amsterdam, The Netherlands, PMID 11810272; 1 case from Robarts Research Institute, Canada, PMID 11668627; 1 case submitted to ClinVar from U4M - Lille University & CHRU Lille, France. One proband with LDLC >10mmol/l and xanthoma, reported by Jiang et al, 2016, Department of atherosclerosis, Capital Medical University, China, PMID 27830735. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Robarts Research Institute, Western University	-	- -
Pathogenic, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Jan 22, 2020	The p.Asn825Lys variant in LDLR has been reported in 75 individuals (including 71 Norweigans, 2 Italian, and 1 Danish, and 1 Dutch individuals) with Familial Hypercholesterolemia, segregated with disease in 71 affected relatives from 19 families (PMID: 15199436, 11810272, 23375686, 11668627, 10532689), and has been identified in 0.001758% (2/113744) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs374045590). Please note that for diseases with clinical variability, or reduced penetrance, pathogenic variants may be present at a low frequency in the general population. This variant has also been reported likely pathogenic and pathogenic in ClinVar (Variation ID: 161265). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. One additional variant with the same amino acid change, c.2475C>A (p.Asn825Lys), has been reported pathogenic and likely pathogenic in association with disease in ClinVar and the literature, supporting that this variant is pathogenic (Variation ID: 252341). In summary, this variant meets criteria to be classified as pathogenic for Familial Hypercholesterolemia in an autosomal dominant manner based on multiple reports of individuals with disease and cosegregation with Familial Hypercholesterolemia. ACMG/AMP Criteria applied: PS4, PP1_Strong, PS1, PP3 (Richards 2015). -
Pathogenic, criteria provided, single submitter	clinical testing	U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille	Mar 30, 2017	- -
Pathogenic, no assertion criteria provided	research	Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Feb 15, 2020	- -
Likely pathogenic, criteria provided, single submitter	literature only	LDLR-LOVD, British Heart Foundation	Mar 25, 2016	- -

Hypercholesterolemia

Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

CSER _CC_NCGL, University of Washington

Jun 01, 2014

- -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Sep 29, 2023

Reported in a patient with atrioventricular block in published literature (Resdal Dyssekilde et al., 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 p.(N804K); This variant is associated with the following publications: (PMID: 25637381, 25487149, 11137106, 11810272, 11668627, 15199436, 23375686, 28323660, 16424354, 17426749, 34407635, 34037665, 19318025, 21310417, 35470684, 10532689, 33740630, 18096825, 27830735, 15576851, 30777337, 37719435, 25378237) -

Cardiovascular phenotype

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 10, 2024

The c.2475C>G (p.N825K) alteration is located in exon 17 (coding exon 17) of the LDLR gene. This alteration results from a C to G substitution at nucleotide position 2475, causing the asparagine (N) at amino acid position 825 to be replaced by a lysine (K). Based on data from gnomAD, the G allele has an overall frequency of 0.001% (2/251458) total alleles studied. The highest observed frequency was 0.002% (2/113744) of European (non-Finnish) alleles. This alteration (also referred to as N804K), and another nucleotide substitution (c.2475C>A) resulting in the same amino acid change have been detected in many individuals from familial hypercholesterolemia cohorts (Jensen, 1999; Leren, 2004; Bertolini, 2013; Chaves, 2001; Brusgaard, 2006; Mozas, 2004). This alteration was also reported to segregate with hypercholesterolemia in several individuals in one family (Berge, 2006). This amino acid position is highly conserved in available vertebrate species. The p.N825K amino acid is located in the FxNPxY motif (Etxebarria, 2015). Experimental studies have indicated this alteration results in impaired LDL internalization and uptake (Etxebarria, 2015; Rodríguez-Jiménez, 2019). The in silico prediction for this alteration is inconclusive. Based on the available evidence, this alteration is classified as pathogenic. -

Familial hypercholesterolemia

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 19, 2023

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: 161265). This variant is also known as N804K. This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 11668627, 18096825, 27765764, 27830735). This variant is present in population databases (rs374045590, gnomAD 0.0009%). 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). Experimental studies have shown that this missense change affects LDLR function (PMID: 25378237). For these reasons, this variant has been classified as Pathogenic. -

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

0.84

D

LIST_S2

Pathogenic

1.0

D;D;D;D;D

M_CAP

Pathogenic

0.78

D

MetaRNN

Pathogenic

0.93

D;D;D;D;D

MetaSVM

Pathogenic

1.0

D

MutationAssessor

Pathogenic

3.2

M;.;.;.;M

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

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

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

Other links and lift over

dbSNP: rs374045590; hg19: chr19-11240274;