rs373646964

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1PM2PM5PP3_StrongPP5

The NM_000527.5(LDLR):c.1474G>A(p.Asp492Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000062 in 1,613,936 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. D492G) has been classified as Likely pathogenic.

Frequency

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

Exomes 𝑓: 0.0000062 ( 0 hom. )

Consequence

LDLR
NM_000527.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:17U:6O:1

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 11 ACMG points.

PM1

In a hotspot region, there are 10 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 10 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 chr19-11113651-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 251865.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.973

PP5

Variant 19-11113650-G-A is Pathogenic according to our data. Variant chr19-11113650-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 161285.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=6, Pathogenic=10, not_provided=1, Uncertain_significance=5}. Variant chr19-11113650-G-A is described in Lovd as [Pathogenic]. Variant chr19-11113650-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.1474G>A	p.Asp492Asn	missense_variant	10/18	ENST00000558518.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LDLR	ENST00000558518.6 linkuse as main transcript	c.1474G>A	p.Asp492Asn	missense_variant	10/18	1	NM_000527.5	P3	P01130-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152198

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000239

AC:

AN:

251420

Hom.:

AF XY:

0.0000368

AC XY:

AN XY:

135896

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000109

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000352

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000616

AC:

AN:

1461738

Hom.:

Cov.:

AF XY:

0.00000963

AC XY:

AN XY:

727176

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000756

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000450

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152198

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74350

show subpopulations

Gnomad4 AFR

AF:

0.0000241

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:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:17Uncertain:6Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hypercholesterolemia, familial, 1

Pathogenic:11Uncertain:4

Likely pathogenic, criteria provided, single submitter	literature only	LDLR-LOVD, British Heart Foundation	Mar 25, 2016	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation	Nov 05, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Robarts Research Institute, Western University	Jan 02, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Nov 07, 2019	Criteria applied: PS3, PS4, PM2_SUP, PP3 -
Likely pathogenic, criteria provided, single submitter	research	Brunham Lab, Centre for Heart and Lung Innovation, University of British Columbia	Dec 06, 2018	- -
Uncertain significance, criteria provided, single submitter	research	Laboratory of Genetics and Molecular Cardiology, University of São Paulo	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	subjects mutated among 2600 FH index cases screened = 10 , family members = 5 with unclear co-segregation / previously described in association with FH/Software predictions: Conflicting -
Likely pathogenic, criteria provided, single submitter	clinical testing	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	Apr 26, 2017	This c.1474G>A (p.Asp492Asn) variant has been reported in a 42 year old male patient with familial hypercholesterolemia from a cohort of 30 patients [reported as D471N, FH Graz-1 in PMID 9763532]. This variant was also reported in a patient presenting with a total cholesterol level of 23 mmol/L and xanthomas [PMID 25936317]; this patient also carried a second allele (p.Gly592Glu), which is classified as pathogenic by our laboratory . This variant was further detected in a patient from a cohort of 2,078 patients from Italy [PMID 23375686]; this patient also carried a p.Cys698Trp variant, classified as a variant of unknown significance by our laboratory at this time. Additional variants affecting the same amino acid at position 492 (p.Asp492Gly and p.Asp492His) have been reported in patients with familial hypercholesterolemia [PMID 16250003, 10208479].This variant was reported in 2 heterozygous individuals in the ExAC database (http://exac.broadinstitute.org/variant/19-11224326-G-A). Asparagine at amino acid position 492 of the LDLR protein is highly conserved in mammals. While not validated for clinical use, the computer-based algorithms predict this p.Asp492Asn change to be deleterious. This variant is thus classified as likely pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory of molecular diagnosis of dyslipidemias, Università egli studi di Napoli Federico II	May 24, 2021	Class 5 - diminished LDLR recycling capacity. -
Uncertain significance, criteria provided, single submitter	research	Fundacion Hipercolesterolemia Familiar	Mar 01, 2016	- -
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	- -
Pathogenic, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Jan 22, 2020	The p.Asp492Asn (p.Asp471Asn) variant in LDLR has been reported in at least 30 individuals (including 13 Italian, 3 Chinese, 2 Norwegian, 2 Taiwanese, 1 Czech, and 1 Saudi Arabian individuals) with Familial Hypercholesterolemia, segregated with disease in up to 14 affected relatives from up to 7 families (PMID: 25647241, 26748104, 29172679, 11737238, 17094996, 23375686, 11005141, 25936317, 15199436, 17539906, 20538126, 9763532, 21310417, 12436241, 19446849; DOI: 10.2217/clp.14.6), and has been identified in 0.01087% (2/18394) of East Asian chromosomes and 0.003518% (4/113704) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs373646964). Please note that for diseases with clinical variability, or reduced penetrance, pathogenic variants may be present at a low frequency in the general population. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. The phenotype of a homozygous individual with this variant is highly specific for Familial Hypercholesterolemia based on xanthomas and family history consistent with disease (DOI: 10.2217/clp.14.6). In summary, this variant meets criteria to be classified as pathogenic for Familial Hypercholesterolemia in an autosomal dominant manner based on multiple reports in individuals with Familial Hypercholesterolemia and cosegregation with disease. ACMG/AMP Criteria applied: PS4, PP1_Moderate, PP3, PP4 (Richards 2015). -
Uncertain significance, criteria provided, single submitter	research	Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge	Mar 01, 2016	0/184 non-FH alleles; 0/100 healthy control individuals -
Pathogenic, criteria provided, single submitter	research	HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	Mar 10, 2020	- -

Familial hypercholesterolemia

Pathogenic:3Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 05, 2017	Variant summary: The LDLR c.1474G>A (p.Asp492Asn) variant involves the alteration of a conserved nucleotide. 4/5 in silico tools predict a damaging outcome for this variant. This variant was found in 2/121480 control chromosomes at a frequency of 0.0000165, which does not exceed the estimated maximal expected allele frequency of a pathogenic LDLR variant (0.0012508). This variant has been reported in multiple affected FH patients including heterozygous patients and compound heterozygous patients (Mak_1998, Chiou_2010, Bertolini_2013, Blaha_2015). Variant was shown to segregate with disease in at least one of the reported families (Blaha_2015). Variants involving nearby nucleotides such as c.1474G>C, c.1474delG, c.1475A>G, etc, have been reported in affected individuals suggesting variant of interest is located in a mutiaotn hotspot. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as likely pathogenic. Taken together, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 08, 2024	This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 492 of the LDLR protein (p.Asp492Asn). This variant is present in population databases (rs373646964, gnomAD 0.01%). This missense change has been observed in individuals with familial hypercholesterolemia and myocardial infarction (PMID: 9763532, 10230472, 11005141, 20236128, 22698793, 23375686, 25487149, 25647241, 25936317, 27680772). It has also been observed to segregate with disease in related individuals. This variant is also known as Asp471Asn and Graz-1. ClinVar contains an entry for this variant (Variation ID: 161285). 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 are conflicting or provide insufficient evidence to determine the effect of this variant on LDLR function (PMID: 25647241). This variant disrupts the p.Asp492 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been observed in individuals with LDLR-related conditions (PMID: 10208479, 16250003), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Feb 01, 2023	This missense variant replaces aspartic acid with asparagine at codon 492 in the third LDLR type B repeat of the EGF precursor homology domain of the LDLR protein. This variant is also known as p.Asp471Asn in the mature protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). A functional study has shown that this variant results in the partially reduced levels of LDLR protein expression at the cell surface, reduced LDL binding, and a defect in LDLR protein recycling (PMID: 35568682). Another study has suggested no to little impact of this variant on LDL uptake (PMID: 25647241). This variant has been observed in over twenty heterozygous individuals affected with familial hypercholesterolemia (PMID: 9763532, 11737238, 12436241, 15199436, 15823288, 17539906, 19318025, 19446849, 20538126, 21310417, 22698793, 25936317, 35249492; Color data) and in two biallelic individuals with severe phenotype (PMID: 25936317, 30592178). This variant has been shown segregate with disease in a family study (PMID: 25936317). This variant has been identified in 6/251420 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Different missense variants occurring at the same position, p.Asp492His and p.Asp492Gly, are known to be disease-causing (ClinVar variation ID: 251864, 251865). Based on the available evidence, this variant is classified as Pathogenic. -
Uncertain significance, criteria provided, single submitter	research	Laboratory of Molecular Genetics, National Medical Research Center for Therapy and Preventive Medicine	-	- -

not provided

Pathogenic:2Other:1

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 21, 2022	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies demonstrate reduced protein expression, receptor binding, and LDL uptake (Galicia-Garcia et al., 2020); Not observed at significant frequency in large population cohorts (gnomAD); Also known as p.D471N and FH-Graz 1; This variant is associated with the following publications: (PMID: 25647241, 27535533, 10230472, 23375686, 25487149, 25637381, 29292049, 27680772, 19446849, 21310417, 22698793, 29172679, 17539906, 26875521, 28965616, 29353225, 25936317, 26748104, 30592178, 31447099, 11005141, 12436241, 15199436, 11737238, 20538126, 20236128, 17094996, 30526649, 32977124, 32041611, 32331935, 33740630, 34037665, 32015373, 26582918, 9763532) -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2022	- -
not provided, no classification provided	in vitro	Dept. of Genetics and Pharmacogenomics, Merck Research Labs	-	- -

Cardiovascular phenotype

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 08, 2024

The p.D492N pathogenic mutation (also known as c.1474G>A), located in coding exon 10 of the LDLR gene, results from a G to A substitution at nucleotide position 1474. The aspartic acid at codon 492 is replaced by asparagine, an amino acid with highly similar properties. This alteration has been reported in the homozygous state in a case with familial hypercholesterolemia (FH), corneal arcus, xanthelasmata, and tendon xanthomas; six heterozygous family members also had elevated cholesterol levels and other clinical symptoms (Faiz F et al. Clin Lipidol., 2014 April; 9:163-170). In addition, compound heterozygotes with this alteration demonstrated clinical symptoms of FH (Blaha M et al. Atheroscler Suppl, 2015 May;18:134-9; Bertolini S et al. Atherosclerosis, 2013 Apr;227:342-8). This alteration, historically known as D471N, has been reported in several FH and myocardial infarction (MI) cohorts (Mak YT et al. Arterioscler. Thromb. Vasc. Biol., 1998 Oct;18:1600-5; Chiou KR et al. Am. J. Cardiol., 2010 Jun;105:1752-8; Tichý L et al. Atherosclerosis, 2012 Aug;223:401-8; Do R et al. Nature, 2015 Feb;518:102-6). The variant was reported in an individual with early-onset MI and CAD with reportedly normal LDL level; however, details were limited. The associated functional study failed to show negative effects for the variant in vitro, but the physiological relevance of the assay results are unclear (Thormaehlen AS et al. PLoS Genet., 2015 Feb;11:e1004855). Another in vitro functional study reported this variant to result in reduced protein expression, activity, and recycling compared to wild type (Galicia-Garcia U et al. Sci Rep. 2020 02;10(1):1727). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Hypercholesterolemia

Uncertain:1

Uncertain significance, no assertion criteria provided

research

CSER _CC_NCGL, University of Washington

Jun 01, 2014

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.84

BayesDel_addAF

Uncertain

0.14

BayesDel_noAF

Pathogenic

0.19

Cadd

Pathogenic

Dann

Pathogenic

1.0

DEOGEN2

Pathogenic

0.92

D;.;.;.;.;.

Eigen

Pathogenic

0.82

Eigen_PC

Pathogenic

0.73

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Pathogenic

1.0

D;D;D;D;D;D

M_CAP

Pathogenic

0.91

MetaRNN

Pathogenic

0.97

D;D;D;D;D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

3.0

M;.;.;.;.;M

MutationTaster

Benign

1.0

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

PrimateAI

Uncertain

0.57

PROVEAN

Pathogenic

-4.7

D;D;D;D;D;D

Sift

Uncertain

0.024

D;D;D;D;D;D

Sift4G

Uncertain

0.024

D;D;D;D;D;D

Polyphen

1.0

D;.;.;.;.;.

Vest4

0.89

MVP

1.0

MPC

0.80

ClinPred

0.94

GERP RS

4.7

Varity_R

0.86

gMVP

0.98

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