rs875989907

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong

The NM_000527.5(LDLR):c.796G>A(p.Asp266Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000031 in 1,614,056 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 Pathogenic (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D266E) has been classified as Pathogenic.

Frequency

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

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

LDLR
NM_000527.5 missense

Scores

Clinical Significance

Pathogenic reviewed by expert panel P:14

Conservation

PhyloP100: 9.99

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 18 ACMG points.

PM1

In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 4 benign, 7 uncertain 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 chr19-11106668-T-A is described in ClinVar as [Pathogenic]. Clinvar id is 161287.Status of the report is reviewed_by_expert_panel, 3 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.996

PP5

Variant 19-11106666-G-A is Pathogenic according to our data. Variant chr19-11106666-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 226334.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr19-11106666-G-A is described in Lovd as [Pathogenic]. Variant chr19-11106666-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LDLR	NM_000527.5 linkuse as main transcript	c.796G>A	p.Asp266Asn	missense_variant	5/18	ENST00000558518.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LDLR	ENST00000558518.6 linkuse as main transcript	c.796G>A	p.Asp266Asn	missense_variant	5/18	1	NM_000527.5	P3	P01130-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152186

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:

0.0000942

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000119

AC:

AN:

251478

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135916

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.0000653

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1461870

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

727240

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152186

Hom.:

Cov.:

AF XY:

0.0000135

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:

0.0000942

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:14

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Hypercholesterolemia, familial, 1

Pathogenic:11

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	U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille	Mar 30, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital	Jan 05, 2022	The LDLR p.Asp266Asn (originally p.Asp245Asn) missense variant occurs within the ligand-binding domain of the LDL-receptor and is pathogenic for familial hypercholesterolaemia (FH). In silico algorithms (PolyPhen2, SIFT, MutationTaster) predict LDLR p.Asp266Asn to be pathogenic. It, along with different missense variants at the same codon (p.Asp266Glu, p.Asp266Gly, p.Asp266Tyr, p.Asp266Val), has previously been identified in multiple cohorts of FH patients worldwide. Studies in cultured patient cells showed that LDL-receptor activity in the homozygous state is <2% of normal (PMID:12414836). -
Pathogenic, reviewed by expert panel	curation	ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	May 04, 2022	The NM_000527.5(LDLR):c. c.796G>A (p.Asp266Asn) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying evidence codes PS4, PM2, PM5_Strong, PS3_Moderate, PP1, PP3 and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755). The supporting evidence is as follows: PS4 - Variant meets PM2. Variant identified in 10 unrelated index cases (1 case fulfilling Simon-Broome criteria published in PMID: 12414836; 1 case probably fulfilling Simon-Broome criteria published in PMID: 12417285; 1 case with DLCN criteria from Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA); 4 cases with Simon-Broome criteria from Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation); 3 cases with DLCN criteria from Mayo Clinic Atherosclerosis and Lipid Genomics Laboratory); PM2 - PopMax MAF = 0.00006533 (0.006533%) in South Asian exomes (gnomAD v2.1.1); PM5_Strong - 4 other missense variants in the same codon: - NM_000527.5(LDLR): c.796G>T (p.Asp266Tyr) (ClinVar ID 251456) - Pathogenic by these guidelines. - NM_000527.5(LDLR): c.797A>T (p.Asp266Val) (ClinVar ID 251458) - Likely Pathogenic by these guidelines. - NM_001195803.2(LDLR):c.797A>G (p.Asp266Gly) (ClinVar ID 251457) - Likely pathogenic by these guidelines. - NM_001195803.2(LDLR): c.798T>A (p.Asp266Glu) - (ClinVar ID 161287) - Pathogenic by these guidelines. There are 2 variants in the same codon classified as Pathogenic by these guidelines. PS3_Moderate - Level 2 assay: PMID 12414836: Homozygous patient cells, 125I assays - result - <2% LDL-LDLR binding and internalisation. Functional study is consistent with damaging effect; PP1 - 3 informative meioses identified by Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation); PP3 - REVEL = 0,83; PP4 - Variant meets PM2. Identified in at least 1 FH case fulfilling Simon-Broome criteria published in PMID 12414836. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation	Nov 05, 2016	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Dec 15, 2021	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix	Dec 16, 2016	subject mutated among 2600 FH index cases screened = 1 , family members = 2 with co-segregation / previously described in association with FH / Software predictions: Damaging -
Likely pathogenic, criteria provided, single submitter	clinical testing	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	Sep 19, 2017	This c.796G>A (p.Asp266Asn) variant in the LDLR gene has been reported in multiple patients with familial hypercholesterolemia (PMID: 11810272, 23375686). Multiple different amino acid substitutions affecting aspartic acid at position 266 of the LDLR protein have also been reported in patients with familial hypercholesterolemia (PMID: 1301956, 12417285, 28235710). The c.796G>A variant is extremely rare in the general population and aspartic acid at position 266 of the LDLR protein is highly evolutionarily conserved. The c.796G>A (p.Asp266Asn) variant in the LDLR gene is classified as likely pathogenic. -
Pathogenic, criteria provided, single submitter	research	Fundacion Hipercolesterolemia Familiar	Mar 01, 2016	- -
Likely pathogenic, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Jan 22, 2020	The p.Asp266Asn (sometimes called p.Asp245Asn) variant in LDLR has been reported in at least 15 individuals (including 8 Norwegian, 3 Tunisian, 1 Dutch, 1 Japanese, and 1 German individuals) with Hypercholesterolemia, segregated with disease in 11 affected relatives from 3 families (PMID: 12414836, 11810272, 15199436, 12417285, 19446849, 14974088), and has been identified in 0.006533% (2/30616) of South Asian chromosomes and 0.005437% (1/18394) of East Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs875989907). 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: 226334). 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 a different amino acid change at the same position (p.Asp266Glu) has been reported in association with disease in ClinVar, supporting that a change at this position may not be tolerated (Variation ID: 161287). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PM5_supporting, PS4_Moderate, PP1_Moderate, PP3 (Richards 2015). -

Homozygous familial hypercholesterolemia

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Apr 16, 2019

The p.Asp266Asn variant in LDLR has been reported in the heterozygous state in 3 individuals with familial hypercholesterolemia (FH), in the homozygous state in 1 individual with a more severe presentation and segregated with disease in 2 affected individuals from 2 families (Fouchier 2001, Slimani 2012, Tichy 2012, Bertolini 2013). It has also been reported by other clinical laboratories in ClinVar (Variation ID 161287) and has identified in 3/251478 pan-ethnic chromosomes by gnomAD (http://gnomad.broadinstitute.org). This frequency is low enough to be consistent with the frequency of FH in the general population. Computational prediction tools and conservation analysis suggest that this variant may impact the protein. In addition, another variant involving this codon (p.Asp266Glu) has been identified in individuals with FH and is classified as pathogenic by this laboratory. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant FH. ACMG/AMP criteria applied: PM2, PM5, PP3, PS4_Supporting. -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Sep 12, 2022

Disrupts a negatively charged triplet, Ser-Asp-Glu, located at the carboxyl-terminal end of the LDL- receptor class A6 repeat domain that is critical for ligand binding (Schneider et al., 2003); 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 FH-Tozeur and p.(D245N); This variant is associated with the following publications: (PMID: 34037665, 30241732, 32331935, 12827279, 23375686, 31447099, 31491741, 33740630, 11810272, 32977124, 12414836, 31386798, 15199436, 14974088, 19446849, 21310417, 22698793, 15823288, 22417841, 26582918, 12417285) -

Familial hypercholesterolemia

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Apr 26, 2023

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Asp266 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 1301956, 11196104, 20663204, 21310417, 22698793, 23375686, 26238499). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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: 226334). This variant is also known as p.Asp245Asn. This missense change has been observed in individuals with hypercholesterolemia (PMID: 14974088, 22417841, 22698793, 23375686). This variant is present in population databases (no rsID available, gnomAD 0.006%). This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 266 of the LDLR protein (p.Asp266Asn). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Uncertain

0.11

BayesDel_noAF

Uncertain

0.11

Cadd

Pathogenic

Dann

Pathogenic

1.0

DEOGEN2

Pathogenic

0.96

D;.;.;.;.

Eigen

Pathogenic

0.87

Eigen_PC

Pathogenic

0.73

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Pathogenic

0.99

D;D;D;D;D

M_CAP

Pathogenic

0.94

MetaRNN

Pathogenic

1.0

D;D;D;D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

4.0

H;.;.;.;H

MutationTaster

Benign

1.0

D;D;D;D;D;D;D

PrimateAI

Uncertain

0.63

PROVEAN

Pathogenic

-4.6

D;D;D;D;D

Sift

Uncertain

0.0010

D;D;D;D;D

Sift4G

Uncertain

0.0040

D;D;D;D;D

Polyphen

1.0

D;.;.;.;.

Vest4

0.85

MutPred

0.94

Loss of disorder (P = 0.1784);Loss of disorder (P = 0.1784);.;.;Loss of disorder (P = 0.1784);

MVP

1.0

MPC

0.79

ClinPred

1.0

GERP RS

5.1

Varity_R

0.99

gMVP

0.99

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

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