rs387906303

Positions:

chr19-11105576-G-A

Variant summary

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

The NM_000527.5(LDLR):c.670G>A(p.Asp224Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000688 in 1,454,426 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. D224A) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

LDLR
NM_000527.5 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:11

Conservation

PhyloP100: 9.88

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 strand (size 2) in uniprot entity LDLR_HUMAN there are 19 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 chr19-11105577-A-C is described in Lovd as [Likely_pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.989

PP5

Variant 19-11105576-G-A is Pathogenic according to our data. Variant chr19-11105576-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3706.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-11105576-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LDLR	NM_000527.5 linkuse as main transcript	c.670G>A	p.Asp224Asn	missense_variant	4/18	ENST00000558518.6	NP_000518.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LDLR	ENST00000558518.6 linkuse as main transcript	c.670G>A	p.Asp224Asn	missense_variant	4/18	1	NM_000527.5	ENSP00000454071	P3	P01130-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.88e-7

AC:

AN:

1454426

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

722792

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:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.02e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hypercholesterolemia, familial, 1

Pathogenic:9

Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 05, 1986	- -
Pathogenic, criteria provided, single submitter	research	Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge	Mar 01, 2016	0/190 non-FH alleles; 0/100 healthy control individuals -
Likely pathogenic, criteria provided, single submitter	clinical testing	Robarts Research Institute, Western University	-	- -
Likely pathogenic, criteria provided, single submitter	literature only	LDLR-LOVD, British Heart Foundation	Mar 25, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Oct 02, 2023	This variant has been reported in multiple individuals with hypercholesterolemia (PMID: 15576851, 19843101, 30876530, 17765246, 16627557, 33231818, 33508743, 20828696, 26020417, 20828696, 33027386). It is absent from large population databases, including the Genome Aggregation Database (http://gnomad.broadinstitute.org/). This variant is located in a well-established protein functional domain where other pathogenic variants have been described. It is predicted to be deleterious by in silico analysis. Functional studies suggest that this variant results in a deleterious effect on the protein (PMID: 30617148, 29874871, 1301956). Other missense substitutions at this amino acid residue have been previously reported in individual(s) with hypercholesterolemia (ClinVar IDs: 1755040, 251375, 251374, 251373), which supports the functional importance of this position. -
Pathogenic, criteria provided, single submitter	research	Fundacion Hipercolesterolemia Familiar	Mar 01, 2016	- -
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 / FH-Portugal -
Pathogenic, no assertion criteria provided	research	Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille	Mar 30, 2017	- -

Cardiovascular phenotype

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 25, 2022

The p.D224N pathogenic mutation (also known as c.670G>A), located in coding exon 4 of the LDLR gene, results from a G to A substitution at nucleotide position 670. The aspartic acid at codon 224 is replaced by asparagine, an amino acid with highly similar properties. This alteration impacts a residue in the conserved cluster of acidic amino acids at the C-terminal end of LDLR class A repeat 5 (Jeon H and Blacklow C. Annu. Rev. Biochem. 2005;74:535-62). This alteration (with legacy nomenclature p.D203N) has been described in the heterozygous and homozygous states in patients with familial hypercholesterolemia (FH), including multiple FH probands from a Portuguese village, three of whom were subsequently shown to be related (Hobbs HH et al. Hum. Mutat., 1992;1:445-66; Wang J et al. J. Lipid Res., 2005 Feb;46:366-72; Blesa S et al. Clin. Chem., 2006 Jun;52:1021-5; Bourbon M et al. Atherosclerosis, 2008 Feb;196:633-42; Gaspar IM et al. Atheroscler Suppl, 2019 Mar;36:28-30). This alteration was also reported in the compound heterozygous state in a patient with severe FH and in a heterozygous state in the proband's affected daughter (Medeiros AM et al. Atherosclerosis, 2010 Oct;212:553-8). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Functional studies suggest this alteration causes reduced LDLR activity (Hobbs HH et al. Hum. Mutat., 1992;1:445-66; Deng SJ et al. J. Lipid Res., 2019 Jan;epub ahead of print). Other alterations affecting the same amino acid, p.D224A, p.D224G, and p.D224V, have also been reported in association with FH (Loubser O et al. Clin. Genet., 1999 May;55:340-5; Hobbs HH et al. Hum. Mutat., 1992;1:445-66; Giesel J et al. Hum. Genet., 1995 Sep;96:301-4). Based on the majority of available evidence to date, this variant is interpreted as a disease-causing mutation. -

Familial hypercholesterolemia

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 06, 2022

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Asp224 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 1301956, 17539906, 23375686). 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: 3706). This variant is also known as D203N. This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 15576851, 19843101, 30876530; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 224 of the LDLR protein (p.Asp224Asn). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.81

BayesDel_addAF

Pathogenic

0.21

BayesDel_noAF

Uncertain

0.070

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.90

D;.;.;.

Eigen

Pathogenic

0.76

Eigen_PC

Pathogenic

0.75

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Pathogenic

0.97

D;D;D;D

M_CAP

Pathogenic

0.64

MetaRNN

Pathogenic

0.99

D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.8

M;.;.;M

MutationTaster

Benign

1.0

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

PrimateAI

Uncertain

0.61

PROVEAN

Pathogenic

-4.5

D;D;D;D

REVEL

Pathogenic

0.83

Sift

Uncertain

0.013

D;D;D;D

Sift4G

Uncertain

0.047

D;T;D;D

Polyphen

1.0

D;.;.;.

Vest4

0.77

MutPred

0.96

Loss of phosphorylation at S226 (P = 0.0983);Loss of phosphorylation at S226 (P = 0.0983);.;Loss of phosphorylation at S226 (P = 0.0983);

MVP

1.0

MPC

0.79

ClinPred

0.99

GERP RS

5.6

Varity_R

0.86

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

Other links and lift over