19-11113650-G-C

Position:

chr19-11113650-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3PP4PM5

This summary comes from the ClinGen Evidence Repository: The NM_000527.5 (LDLR):c.1474G>C (p.Asp492His) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2, PM5, PP3 and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 7 November 2023.The supporting evidence is as follows:PM2: PopMax MAF=0.00002 in Non-Finnish European population in gnomAD (gnomAD v2.1.1).PP3: REVEL=0.993.PM5: Two other missense variants in the same codon: NM_000527.5(LDLR):c.1474G>A (p.Asp492Asn), ClinVar 161285, classified as Pathogenic by these guidelines; NM_000527.5(LDLR):c.1475A>G (p.Asp492Gly), ClinVar 251865, classified as Likely Pathogenic by these guidelines. Therefore PM5 is met.PP4: Variant meets PM2 and is identified in 1 index case who fulfils Simon Broome criteria for FH diagnosis after alternative causes of high cholesterol were excluded, reported in PMID 10208479 (Heath et al., 1999), from University College London Medical School, UK. LINK:https://erepo.genome.network/evrepo/ui/classification/CA10585474/MONDO:0007750/013

Frequency

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

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

LDLR
NM_000527.5 missense

Scores

Clinical Significance

Likely pathogenic reviewed by expert panel 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 Likely_pathogenic. Variant got 6 ACMG points.

PM2

For more information check the summary or visit ClinGen Evidence Repository.

PM5

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.1474G>C	p.Asp492His	missense_variant	10/18	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.1474G>C	p.Asp492His	missense_variant	10/18	1	NM_000527.5	ENSP00000454071.1		P01130-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152198

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:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251420

Hom.:

AF XY:

0.00000736

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:

0.00

Gnomad SAS 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:

AN:

1461738

Hom.:

Cov.:

AF XY:

0.00000275

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:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000360

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:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000307

Hom.:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:11

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Hypercholesterolemia, familial, 1

Pathogenic:4

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	- -
Likely pathogenic, reviewed by expert panel	curation	ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	Nov 07, 2023	The NM_000527.5 (LDLR):c.1474G>C (p.Asp492His) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2, PM5, PP3 and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 7 November 2023. The supporting evidence is as follows: PM2: PopMax MAF=0.00002 in Non-Finnish European population in gnomAD (gnomAD v2.1.1). PP3: REVEL=0.993. PM5: Two other missense variants in the same codon: NM_000527.5(LDLR):c.1474G>A (p.Asp492Asn), ClinVar 161285, classified as Pathogenic by these guidelines; NM_000527.5(LDLR):c.1475A>G (p.Asp492Gly), ClinVar 251865, classified as Likely Pathogenic by these guidelines. Therefore PM5 is met. PP4: Variant meets PM2 and is identified in 1 index case who fulfils Simon Broome criteria for FH diagnosis after alternative causes of high cholesterol were excluded, reported in PMID 10208479 (Heath et al., 1999), from University College London Medical School, UK. -
Likely pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Sep 23, 2024	The c.1474G>C (p.Asp492His) variant, also known as p.Asp471His in LDLR gene, that encodes for low density lipoprotein receptor, has been identified in at least four individuals affected with familial hypercholesterolemia (FH) (PMID:10208479, 11313767, 15556093, 16389549) and three individuals referred for genetic testing due to clinical suspicion of FH (PMID: 34037665). This variant has also been reported in an individual affected with myocardial infarction (PMID: 30586733). In-silico computational prediction tools suggest that the p.Asp492His variant may have deleterious effect on the protein function (REVEL score: 0.993). This variant is rare (5/1613936 chromosomes; 0.0003098%) in the general population database, gnomAD and interpreted as likely pathogenic by multiple submitters in the ClinVar database (ClinVar ID: 251864). Other missense variants affecting the same amino acid, p.Asp492Asn and p.Asp492Gly, have been reported in numerous individuals affected with FH and classified as pathogenic by several ClinVar submitters (ClinVar ID: 161285, 251865). Therefore, the c.1474G>C (p.Asp492His) variant in LDLR gene is classified as likely pathogenic. -

not provided

Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Feb 14, 2024	Also reported in a patient with early-onset myocardial infarction; however, additional clinical data including cholesterol levels were not provided (PMID: 30586733); 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 D471H; This variant is associated with the following publications: (PMID: 15556093, 30586733, 32719484, 34037665, 10208479, 11373616, 16389549, 11313767) -
Likely pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jun 21, 2024	PP3, PM2, PM5, PS4_moderate -
Likely pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jul 12, 2023	The LDLR c.1474G>C (p.Asp492His) variant has been reported in the published literature in affected individuals and families with familial hypercholesterolemia or early-onset myocardial infarction (PMIDs: 16389549 (2006), 10208479 (1999), 30586733 (2019), 31993549 (2020), and 34037665 (2021)). The frequency of this variant in the general population, 0.0000071 (2/282806 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, this variant is classified as likely pathogenic. -

Familial hypercholesterolemia

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 11, 2024	This sequence change replaces aspartic acid, which is acidic and polar, with histidine, which is basic and polar, at codon 492 of the LDLR protein (p.Asp492His). This variant is present in population databases (no rsID available, gnomAD 0.002%). This missense change has been observed in individuals with clinical features of familial hypercholesterolemia (PMID: 10208479; Invitae). This variant is also known as p.Asp471His (D471H). ClinVar contains an entry for this variant (Variation ID: 251864). 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%. This variant disrupts the p.Asp492 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9763532, 10230472, 16250003, 23375686, 25487149, 25936317). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jun 07, 2021	This missense variant (also known as p.Asp471His in the mature protein) is located in the LDLR type B repeat 3 of the EGF precursor homology domain of the LDLR protein. This variant changes a highly conserved Asp residue within the functionally important YWTD motif. Computational prediction tools and conservation analyses suggest that this variant may have deleterious impact on the protein function. Computational splicing tools suggest that this variant may not impact the RNA splicing. To our knowledge, functional assays have not been performed for this variant. This variant has been reported in individuals affected with familial hypercholesterolemia in UK (PMID: 10208479, 15556093, 16389549, 31993549). This variant has been identified in 2/277190 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Different missense variants at the same position (p.Asp492Asn and p.Asp492Gly) are considered to be disease-causing. Based on available evidence, this variant is classified as Likely Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 12, 2022	Variant summary: LDLR c.1474G>C (p.Asp492His) results in a non-conservative amino acid change located in the LDLR class B repeat domain (IPR000033) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.9e-06 in 258942 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1474G>C has been reported in the literature in individuals affected with Familial Hypercholesterolemia (Heath_1999, Khera_2019). In addition, other missense changes at this position, p.Asp492Asn and p.Asp492Gly, and nearby codons, p.Thr491Asn, p.Gly496Asp, p.Gly496Val, p.Thr497Pro, have been reported as pathogenic, suggesting this region is important for protein function. Furthermore, Jeon_2001, reports that mutations in this region are likely to disrupt the structure of the propeller and prevent efficient transport of the receptor to the cell surface leading to Familial Hypercholesterolemia. These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and a predominant consensus as pathogenic/likely pathogenic (n=3) (VUS, n=1). Most submitters cite overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Cardiovascular phenotype

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 21, 2022

The p.D492H variant (also known as c.1474G>C), located in coding exon 10 of the LDLR gene, results from a G to C substitution at nucleotide position 1474. The aspartic acid at codon 492 is replaced by histidine, an amino acid with similar properties. This variant, historically known as p.D471H, has been reported in familial hypercholesterolemia (FH) and early onset myocardial infarction (MI) cohorts (Heath KE et al. Atherosclerosis, 1999 Mar;143:41-54; Sozen M et al. Atheroscler Suppl, 2004 Dec;5:7-11; Khera AV et al. Circulation, 2019 Mar;139:1593-1602; Sturm AC et al. JAMA Cardiol, 2021 08;6:902-909). Alterations affecting the same amino acid (p.D492N and p.D492G) have also been described in association with FH (Mak YT et al. Arterioscler. Thromb. Vasc. Biol., 1998 Oct;18:1600-5; Fouchier SW et al. Hum. Mutat., 2005 Dec;26:550-6). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.59

BayesDel_noAF

Pathogenic

0.60

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.98

D;.;.;.;.;.

Eigen

Pathogenic

0.96

Eigen_PC

Pathogenic

0.82

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Pathogenic

1.0

D;D;D;D;D;D

M_CAP

Pathogenic

0.96

MetaRNN

Pathogenic

1.0

D;D;D;D;D;D

MetaSVM

Pathogenic

0.95

MutationAssessor

Pathogenic

4.4

H;.;.;.;.;H

PrimateAI

Uncertain

0.59

PROVEAN

Pathogenic

-6.5

D;D;D;D;D;D

REVEL

Pathogenic

0.99

Sift

Uncertain

0.0010

D;D;D;D;D;D

Sift4G

Uncertain

0.0020

D;D;D;D;D;D

Polyphen

1.0

D;.;.;.;.;.

Vest4

0.97

MutPred

0.99

Loss of sheet (P = 0.1907);Loss of sheet (P = 0.1907);.;.;.;Loss of sheet (P = 0.1907);

MVP

1.0

MPC

0.88

ClinPred

1.0

GERP RS

4.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.99

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

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