rs376459828

Variant summary

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

The NM_000527.5(LDLR):c.590G>A(p.Cys197Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000434 in 1,613,898 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. C197F) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

LDLR
NM_000527.5 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:22

Conservation

PhyloP100: 7.52

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 hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 11 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 chr19-11105496-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 251309.Status of the report is reviewed_by_expert_panel, 3 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.995

PP5

Variant 19-11105496-G-A is Pathogenic according to our data. Variant chr19-11105496-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 200919.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-11105496-G-A is described in Lovd as [Pathogenic]. Variant chr19-11105496-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.590G>A	p.Cys197Tyr	missense_variant	4/18	ENST00000558518.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LDLR	ENST00000558518.6 linkuse as main transcript	c.590G>A	p.Cys197Tyr	missense_variant	4/18	1	NM_000527.5	P3	P01130-1

Frequencies

GnomAD3 genomes

AF:

0.0000328

AC:

AN:

152246

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

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:

0.00143

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461652

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727146

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

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:

0.00

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000328

AC:

AN:

152246

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74376

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000131

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:

0.00143

Alfa

AF:

0.0000239

Hom.:

Bravo

AF:

0.0000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:22

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hypercholesterolemia, familial, 1

Pathogenic:12

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	clinical testing	All of Us Research Program, National Institutes of Health	Jan 10, 2024	This missense variant is located in the fifth LDLR type A repeat of the ligand binding domain of the LDLR protein. This variant is also known as p.Cys176Tyr in the mature protein sequence and as FH El Salvador-1 in the literature. This variant alters a conserved cysteine residue that is critical for proper protein folding and function (PMID: 2088165, 6091915, 15952897). Computational prediction tool suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >=0.7, PMID: 27666373). Cells from an individual compound heterozygous for this variant and p.Gln678\* showed <2% LDLR activity (PMID: 1301956). This variant has been reported in over ten individuals affected with familial hypercholesterolemia (PMID: 1301956, 18096825, 20538126, 21376320, 23064986, 27765764, 27816806, 28502495, 32044282, 37119068). This variant has been reported in five heterozygous and two homozygous individuals from a family affected with familial hypercholesterolemia, with the two homozygotes having coronary artery disease and myocardial infarction (PMID: 27816806). It has also been reported in homozygous state in an individual affected with severe homozygous familial hypercholesterolemia (PMID: 34029164). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Different missense variants occurring at the same amino acid position (p.Cys197Gly, p.Cys197Phe, and p.Cys197Trp) are known to be disease-causing (ClinVar variation ID: 251308, 251309, 251311), indicating that cysteine at this position is important for LDLR function. Based on the available evidence, this variant is classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	literature only	LDLR-LOVD, British Heart Foundation	Mar 25, 2016	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Dec 06, 2019	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Robarts Research Institute, Western University	-	- -
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-El-Savador, <2% activy LDLR / Software predictions: Damaging -
Likely pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 14, 2021	- -
Likely pathogenic, criteria provided, single submitter	research	Fundacion Hipercolesterolemia Familiar	Mar 01, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Mar 01, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	New York Genome Center	Jul 12, 2023	The c.590G>A variant in LDLR has been reported in many individuals with hypercholesterolemia (also known as El Salvador type) in both heterozygous and biallelic states [PMID: 1301956, 27816806, 34040191, 33740630, 34037665, 33994402] and deposited in ClinVar [ClinVar ID: 200919] as Pathogenic by multiple submitters. The c.590G>A variant is observed in 14 alleles (~0.0033% minor allele frequency with 0 homozygotes) in population databases (gnomAD v3.1.2, TOPMed Freeze 8), suggesting it is not a common benign variant in the populations represented in those databases. The c.590G>A variant in LDLR is located in exon 4 of this 18-exon gene, and is predicted to replace an evolutionarily conserved cysteine amino acid with tyrosine at position 197 in the LDL-receptor class A repeat 5 (aa195-233) region of the encoded protein [UniProt ID: P01130]. In silico predictions are in favor of damaging effect for the p.(Cys197Tyr) variant [(CADD v1.6 = 24.3, REVEL = 0.936)]. The LDL receptor activity was found less than 2% in an individual with hypercholesterolemia carrying this variant with a stop-gain variant [PMID: 1301956]. Other variants affecting the p.Cys197 residue have also been reported in individuals with hypercholesterolemia [PMID: 28349240]. Based on available evidence this c.590G>A p.(Cys197Tyr) variant identified in LDLR is classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	research	Iberoamerican FH Network	Mar 01, 2016	- -

not provided

Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	May 20, 2019	PS3_moderate, PS4, PM1, PM2, PM5, PP3 -
Likely pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jun 19, 2023	The LDLR c.590G>A (p.Cys197Tyr) variant has been reported in the published literature in multiple individuals with familial hypercholesterolemia (PMIDs: 1301956 (1992), 18096825 (2008), 19717150 (2010), 20538126 (2010), 21276076 (2011), 23064986 (2012), 27816806 (2016), 27765764 (2016), 28502495 (2017), 34037665 (2021), and 33994402 (2021)). Experimental studies have shown that this variant has a damaging effect on protein folding, maturation, and finally results in reduced LDLR activity (PMIDs: 1301956 (1992) and 14993243 (2004)). The frequency of this variant in the general population, 0.000032 (1/31400 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with 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 pathogenic. -
Likely pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Familial hypercholesterolemia

Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 04, 2019	Variant summary: LDLR c.590G>A (p.Cys197Tyr), also known as FH-El Salvador-1, results in a non-conservative amino acid change located in the Low-density lipoprotein (LDL) receptor class A repeat domain (IPR002172) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 246122 control chromosomes. c.590G>A has been reported in the literature in multiple individuals affected with Familial Hypercholesterolemia (Hobbs_1992; Ahmad_2012; Junyent_2010; Setia_2016; Chious_2011; Martin-Campos_2018). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <2% of normal LDLR activity (Hobbs_1992). Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 197 of the LDLR protein (p.Cys197Tyr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 1301956, 18096825, 20538126, 21276076, 23064986, 27765764, 27816806). This variant is also known as p.Cys176Tyr. ClinVar contains an entry for this variant (Variation ID: 200919). 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 affects a cysteine residue located within an LDLRA or epidermal-growth-factor (EGF)-like domains of the LDLR protein. Cysteine residues in these domains have been shown to be involved in the formation of disulfide bridges, which are critical for protein structure and stability (PMID: 7548065, 7603991, 7979249). In addition, missense substitutions within the LDLRA and EGF-like domains affecting cysteine residues are overrepresented among patients with hypercholesterolemia (PMID: 18325082). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	Aug 09, 2021	The c.590G>A (p.Cys197Tyr) variant, also known as p.Cys176Tyr in LDLR gene that encodes for low density lipoprotein receptor, has been identified in at least ten individuals affected with familial hypercholesterolemia (FH) (PMID: 18096825, 20538126, 21376320, 23064986, 27765764, 28502495, 32044282, 21276076, 33994402, 30293936). This variant has also been observed in homozygous status in two individuals in a family with coronary artery disease (PMID: 27816806), and five individuals with homozygous FH (PMID: 37119068, 27365335). Fibroblasts derived from an individual harboring this variant in compound heterozygous status (with p.Gln678*) revealed <2% LDLR activity (PMID: 1301956). This variant lies in the well-established LDL binding domain (amino acids 105-232) critical for protein function and affects the Cysteine residue essential for disulfide bond formation (PMID: 2600087). In-silico computational prediction tools suggest that the p.Cys197Tyr variant may have deleterious effect on the protein function (REVEL score: 0.936). This variant is found to be rare (1/31400; 0.00003185) in the general population database, gnomAD and interpreted as likely pathogenic/pathogenic by several submitters in the ClinVar database (ClinVar ID: 200919). Therefore, the c.590G>A (p.Cys197Tyr) variant in LDLR gene is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Sep 08, 2023	This missense variant is located in the fifth LDLR type A repeat of the ligand binding domain of the LDLR protein. This variant is also known as p.Cys176Tyr in the mature protein sequence and as FH El Salvador-1 in the literature. This variant alters a conserved cysteine residue that is critical for proper protein folding and function (PMID: 2088165, 6091915, 15952897). Computational prediction tool suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >=0.7, PMID: 27666373). Cells from an individual compound heterozygous for this variant and p.Gln678\* showed <2% LDLR activity (PMID: 1301956). This variant has been reported in over ten individuals affected with familial hypercholesterolemia (PMID: 1301956, 18096825, 20538126, 21376320, 23064986, 27765764, 27816806, 28502495, 32044282, 37119068). This variant has been reported in five heterozygous and two homozygous individuals from a family affected with familial hypercholesterolemia, with the two homozygotes having coronary artery disease and myocardial infarction (PMID: 27816806). It has also been reported in homozygous state in an individual affected with severe homozygous familial hypercholesterolemia (PMID: 34029164). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Different missense variants occurring at the same amino acid position (p.Cys197Gly, p.Cys197Phe, and p.Cys197Trp) are known to be disease-causing (ClinVar variation ID: 251308, 251309, 251311), indicating that cysteine at this position is important for LDLR function. Based on the available evidence, this variant is classified as Pathogenic. -

Homozygous familial hypercholesterolemia

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Dec 17, 2021

The p.Cys197Tyr variant in LDLR has been reported in the heterozygous, compound heterozygous, or homozygous state in at least 10 individuals with familial hypercholesterolemia (FH) and segregated with disease in at least 2 affected individuals from 2 families (Hobbs 1992 PMID: 1301956, Setia 2016 PMID: 27816806, Chiou 2010 PMID: 20538126, Junyent 2008 PMID: 18096825, Ahmad 2012 PMID: 23064986, Wang 2016 PMID: 27765764, Khera 2019 PMID: 30586733, Setia 2020 PMID: 32044282, Dron 2020 PMID: 32041611, Orringer 2020 PMID 32505727, LMM data). It has also been identified in 0.01% (2/15282) of Latino chromosomes in gnomAD (http://gnomad.broadinstitute.org) and has been reported in ClinVar (Variation ID 200919). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In vitro functional studies also support that this variant impacts protein function (Hobbs 1992 PMID: 1301956). This variant occurs in a critical cysteine residue involved in disulfide bond formation, where the majority of pathogenic variants in this gene have been identified. Additional variants involving this codon (p.Cys197Gly, p.Cys197Phe, p.Cys197Trp) have been identified in individuals with FH. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant FH. ACMG/AMP Criteria applied: PS4, PM1, PM3, PM5, PM2_Supporting, PP3. -

Cardiovascular phenotype

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 01, 2021

The p.C197Y pathogenic mutation (also known as c.590G>A), located in coding exon 4 of the LDLR gene, results from a G to A substitution at nucleotide position 590. The cysteine at codon 197, located in LDLR class A repeat 5, is replaced by tyrosine, an amino acid with highly dissimilar properties. Pathogenic LDLR mutations that result in the substitution or generation of cysteine residues within the cysteine-rich LDLR class A repeats and EGF-like domains are common in familial hypercholesterolemia (FH) (Villéger L. Hum Mutat. 2002;20(2):81-7). This particular alteration, also referred to as FH El Salvador-1 or C176Y, has been reported in individuals with FH and has demonstrated reduced LDLR activity (Hobbs HH et al. Hum. Mutat., 1992;1:445-66; Junyent M et al. Atherosclerosis, 2010 Feb;208:437-41; Chiou KR et al. Am. J. Cardiol., 2010 Jun;105:1752-8; Martinez M et al. Am J Cardiol, 2016 08;118:504-10; Setia N et al. Atherosclerosis, 2016 Dec;255:31-36; Martín-Campos JM et al. J Clin Lipidol 2018 Oct;12:1452-1462). Internal structural analysis indicates this alteration eliminates a disulfide bond critical for the structural integrity of LDLR class A repeat 5. In addition, alterations affecting the same amino acid (C197F, C197W, C197G, C197R) have also been described in FH (Hobbs HH et al. Hum. Mutat., 1992;1:445-66; Chmara M et al. J Appl Genet. 2010;51(1):95-106; Marduel M et al. Hum. Mutat., 2010 Nov;31:E1811-24; Webb JC et al. J. Lipid Res., 1996 Feb;37:368-81). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.97

BayesDel_addAF

Pathogenic

0.57

BayesDel_noAF

Pathogenic

0.59

Cadd

Uncertain

Dann

Uncertain

0.98

DEOGEN2

Pathogenic

0.97

D;.;.;.

Eigen

Pathogenic

0.78

Eigen_PC

Uncertain

0.60

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Benign

0.79

T;T;T;T

M_CAP

Pathogenic

0.92

MetaRNN

Pathogenic

1.0

D;D;D;D

MetaSVM

Pathogenic

0.95

MutationAssessor

Pathogenic

4.5

H;.;.;H

MutationTaster

Benign

1.0

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

PrimateAI

Uncertain

0.60

PROVEAN

Pathogenic

-8.8

D;D;D;D

Sift

Pathogenic

0.0

D;D;D;D

Sift4G

Pathogenic

0.0

D;D;D;D

Polyphen

1.0

D;.;.;.

Vest4

0.93

MutPred

0.98

Loss of catalytic residue at P196 (P = 0.0064);Loss of catalytic residue at P196 (P = 0.0064);.;Loss of catalytic residue at P196 (P = 0.0064);

MVP

1.0

MPC

1.1

ClinPred

1.0

GERP RS

4.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Varity_R

0.99

gMVP

1.0

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