NM_000527.5:c.1774G>A

Variant names:

• chr19-11116927-G-A
• rs763147599
• NM_000527.5:c.1774G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM5 PM2 PP3 PP4 PS4_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
• Clinical Significance: Likely pathogenic reviewed by expert panel P:9
• Conservation: PhyloP100: 9.86
• Publications: 4 publications found

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 Gene-Disease associations (from GenCC):

• hypercholesterolemia, familial, 1

  Inheritance: AD, SD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, ClinGen
• homozygous familial hypercholesterolemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000527.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LDLR	NM_000527.5	MANE Select	c.1774G>A	p.Gly592Arg	missense	Exon 12 of 18	NP_000518.1
	LDLR	NM_001195798.2		c.1774G>A	p.Gly592Arg	missense	Exon 12 of 18	NP_001182727.1
	LDLR	NM_001195799.2		c.1651G>A	p.Gly551Arg	missense	Exon 11 of 17	NP_001182728.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LDLR	ENST00000558518.6	TSL:1 MANE Select	c.1774G>A	p.Gly592Arg	missense	Exon 12 of 18	ENSP00000454071.1
	LDLR	ENST00000252444.10	TSL:1	c.2032G>A	p.Gly678Arg	missense	Exon 12 of 18	ENSP00000252444.6
	LDLR	ENST00000558013.5	TSL:1	c.1774G>A	p.Gly592Arg	missense	Exon 12 of 18	ENSP00000453346.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000159 AC: 4 AN: 251478 AF XY: 0.0000294

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 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

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000580 AC: 5 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53408

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111844

Other (OTH) AF: 0.00 AC: 0 AN: 60390

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.0000247 AC: 3

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:9

Revision: reviewed by expert panel

Submissions by phenotype

Hypercholesterolemia, familial, 1 Pathogenic:4

Dec 16, 2016

Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Mar 30, 2017

U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Aug 28, 2022

ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel

Significance: Likely pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

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.

Feb 07, 2023

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

proposed classification - variant undergoing re-assessment, contact laboratory

Familial hypercholesterolemia Pathogenic:2

Dec 30, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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, 33732287, 33740630, 34428338, 35910211). This variant is also known as c.1393G>A (p.Gly465Arg). ClinVar contains an entry for this variant (Variation ID: 373769). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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.

Sep 14, 2022

Color Diagnostics, LLC DBA Color Health

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

LDLR-related disorder Pathogenic:1

May 16, 2024

PreventionGenetics, part of Exact Sciences

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

Apr 25, 2023

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

May 14, 2025

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1774G>A (p.G592R) alteration is located in exon 12 (coding exon 12) of the LDLR gene. This alteration results from a G to A substitution at nucleotide position 1774, causing the glycine (G) at amino acid position 592 to be replaced by an arginine (R). Based on data from gnomAD, the A allele has an overall frequency of 0.002% (4/251478) total alleles studied. The highest observed frequency was 0.01% (3/30616) of South Asian alleles. Another variant at the same codon, c.1775G>A (p.G592E) has been identified in individual(s) with features consistent with familial hypercholesterolemia (Tichý, 2012). This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as likely pathogenic.

Computational scores

Source: dbNSFP v4.9

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
M_CAP	Pathogenic	0.90	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.1	H
PhyloP100		9.9
PrimateAI	Uncertain	0.56	T
PROVEAN	Pathogenic	-7.6	D
REVEL	Pathogenic	0.95
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.93
MutPred		0.95		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
Mutation Taster		=0/100	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs763147599; hg19: chr19-11227603;