chr19-11116927-G-A

Position:

chr19-11116927-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2PM5PP3PP4PS4_Supporting

This summary comes from the ClinGen Evidence Repository: The NM_000527.4(LDLR):c.1774G>A (p.Gly592Arg) variant is classified as Likely pathogenic for Familial Hypercholesterolemia by applying evidence codes PM2, PM5, PP3, PS4_Supportign and PP4 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 = 0.00009799 (0.0098%) in South Asian exomes (gnomAD v2.1.1). It is below 0.02%, so PM2 is met.PM5 - 1 other missense variant in the same codon, NM_000527.5(LDLR):c.1775G>A (p.Gly592Glu) - classified as Pathogenic by the FH VCEP, so PM5 is met.PP3 - REVEL = 0.951. It is above 0.75, so PP3 is met.PS4_supporting - variant meets PM2 and was identified in 3 index cases with Dutch Lipid Clinic Scoring : Definite FH from U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille (Accession: SCV000583882.1 in ClinVar), so PS4_Supporting is met.PP4 - variant meets PM2 and was identified in 3 index cases with clinical FH criteria (please see PS4 for details), so PP4 is met. LINK:https://erepo.genome.network/evrepo/ui/classification/CA036598/MONDO:0007750/013

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

LDLR
NM_000527.5 missense

Scores

14

4

1

Clinical Significance

Likely pathogenic reviewed by expert panel P:9

Conservation

PhyloP100: 9.86

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 7 ACMG points.

PS4

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

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.1774G>A	p.Gly592Arg	missense_variant	12/18	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.1774G>A	p.Gly592Arg	missense_variant	12/18	1	NM_000527.5	ENSP00000454071	P3	P01130-1

Frequencies

GnomAD3 genomes

Cov.:

32

GnomAD3 exomes

AF:

0.0000159

AC:

4

AN:

251478

Hom.:

0

AF XY:

0.0000294

AC XY:

4

AN XY:

135914

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:

0.0000980

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000410

AC:

6

AN:

1461696

Hom.:

0

Cov.:

34

AF XY:

0.00000825

AC XY:

6

AN XY:

727154

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:

0.0000580

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

32

ExAC

AF:

0.0000247

AC:

3

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:9

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Hypercholesterolemia, familial, 1

Pathogenic:4

Likely pathogenic, reviewed by expert panel	curation	ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	Aug 28, 2022	The NM_000527.4(LDLR):c.1774G>A (p.Gly592Arg) variant is classified as Likely pathogenic for Familial Hypercholesterolemia by applying evidence codes PM2, PM5, PP3, PS4_Supportign and PP4 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 = 0.00009799 (0.0098%) in South Asian exomes (gnomAD v2.1.1). It is below 0.02%, so PM2 is met. PM5 - 1 other missense variant in the same codon, NM_000527.5(LDLR):c.1775G>A (p.Gly592Glu) - classified as Pathogenic by the FH VCEP, so PM5 is met. PP3 - REVEL = 0.951. It is above 0.75, so PP3 is met. PS4_supporting - variant meets PM2 and was identified in 3 index cases with Dutch Lipid Clinic Scoring : Definite FH from U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille (Accession: SCV000583882.1 in ClinVar), so PS4_Supporting is met. PP4 - variant meets PM2 and was identified in 3 index cases with clinical FH criteria (please see PS4 for details), so PP4 is met. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 07, 2023	proposed classification - variant undergoing re-assessment, contact laboratory -
Pathogenic, criteria provided, single submitter	clinical testing	U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille	Mar 30, 2017	- -
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	- -

Familial hypercholesterolemia

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Sep 14, 2022	This missense variant (also known as p.Gly571Arg in the mature protein and as p.Gly465Arg based on a different transcript NM_001195803.2) replaces glycine with arginine at codon 592 in the fifth LDLR type B repeat of the LDLR 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in eight individuals affected with familial hypercholesterolemia including one homozygote with premature coronary artery disease (PMID: 27932355, 33732287, 35910211, ClinVar SCV000503411.1, SCV002568019.1). This variant has also been observed in two unaffected individuals (PMID: 27050191, 35910211). This variant has been identified in 4/251478 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different missense variant occurring at the same codon, p.Gly592Glu, is known to cause disease (Clinvar variation ID:161271), indicating that glycine at this position is important for the protein function. Based on the available evidence, this variant is classified as Likely Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 17, 2023	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 592 of the LDLR protein (p.Gly592Arg). This variant is present in population databases (rs763147599, gnomAD 0.01%). This missense change has been observed in individual(s) with hypercholesterolemia (PMID: 27932355, 33740630, 35910211). This variant is also known as c.1393G>A (p.Gly465Arg). ClinVar contains an entry for this variant (Variation ID: 373769). 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.Gly592 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15864114, 20663204, 21310417, 21925044, 23375686, 26238499). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

LDLR-related disorder

Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 16, 2024

The LDLR c.1774G>A variant is predicted to result in the amino acid substitution p.Gly592Arg. This variant has been reported in the heterozygous state in individuals with hypercholesterolemia (reported as c.1393G>A in Table S3, Li et al. 2017. PubMed ID: 27932355; Table S3, Leren et al. 2021. PubMed ID: 33740630; Diboun et al. 2022. PubMed ID: 35910211) and reported in two individuals from the Homozygous Familial Hypercholesterolemia (HoFH) International Clinical Collaborators registry (Table S3, Tromp et al. 2022. PubMed ID: 35101175). It has also been reported in an unaffected individual (Online table 4, Khera et al. 2016. PubMed ID: 27050191). This variant is reported in 0.0098% of alleles in individuals of South Asian descent in gnomAD. Another nucleotide change affecting this amino acid (p.Gly592Glu) has been reported in individuals with familial hypercholesterolemia (Hobbs et al. 1992. PubMed ID: 1301956). This variant is interpreted as likely pathogenic. -

not provided

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Quest Diagnostics Nichols Institute San Juan Capistrano

Apr 25, 2023

The frequency of this variant in the general population, 0.000098 (3/30616 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in individuals with familial hypercholesterolemia (PMIDs: 35910211 (2022), 33740630 (2021), 27932355 (2017)) and coronary artery disease (CAD) (PMID: 27050191 (2016)). 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. -

Cardiovascular phenotype

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 30, 2016

The p.G592R variant (also known as c.1774G>A), located in coding exon 12 of the LDLR gene, results from a G to A substitution at nucleotide position 1774. The glycine at codon 592 is replaced by arginine, an amino acid with dissimilar properties. In a study investigating the impact familial hypercholesterolemia (FH) mutations have on coronary artery disease (CAD) risk, this alteration was reported in a individual without CAD, but clinical details on individual cholesterol levels were limited (Khera AV et al. J. Am. Coll. Cardiol. 2016;67:2578-89). One of the most common disease-causing mutations in LDLR, p.G592E, has been described in the same codon (Tichý L et al. Atherosclerosis. 2012;223:401-8). Based on data from ExAC, the A allele has an overall frequency of less than 0.01% (3/106204). 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

0.81

BayesDel_addAF

Pathogenic

0.44

D

BayesDel_noAF

Pathogenic

0.60

CADD

Pathogenic

28

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.97

D;.;.;.;.;.

Eigen

Pathogenic

0.72

Eigen_PC

Uncertain

0.55

FATHMM_MKL

Pathogenic

0.99

D

LIST_S2

Pathogenic

1.0

D;D;D;D;D;D

M_CAP

Pathogenic

0.90

D

MetaRNN

Pathogenic

0.99

D;D;D;D;D;D

MetaSVM

Pathogenic

1.0

D

MutationAssessor

Pathogenic

4.1

H;.;.;.;.;H

MutationTaster

Benign

1.0

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

PrimateAI

Uncertain

0.56

T

PROVEAN

Pathogenic

-7.6

D;D;D;D;D;D

REVEL

Pathogenic

0.95

Sift

Uncertain

0.0010

D;D;D;D;D;D

Sift4G

Pathogenic

0.0010

D;D;D;D;D;D

Polyphen

1.0

D;.;.;.;.;.

Vest4

0.93

MutPred

0.95

Loss of sheet (P = 0.0357);Loss of sheet (P = 0.0357);.;.;.;Loss of sheet (P = 0.0357);

MVP

1.0

MPC

0.89

ClinPred

1.0

D

GERP RS

5.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.95

gMVP

0.98

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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: rs763147599; hg19: chr19-11227603;