rs557344672

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM2PM1PP4PS3_ModeratePS4_Moderate

This summary comes from the ClinGen Evidence Repository: The NM_000527.5(LDLR):c.542C>G (p.Pro181Arg) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM1, PM2, PS3_Moderate, PS4_Moderate and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 23 February 2024. The supporting evidence is as follows: PM2: PopMax MAF = 0.00005 (0.005%) in European (Non-Finnish) exomes+genomes (gnomAD v4.0.0). PM1: Variant meets PM2 and is a missense in exon 4. PS3_Moderate: Level 2 assay: PMID 21868016 (Garcia-Garcia A et al., 2011): COS-7 cells. Mature/precursor LDLR forms ratio ~60% ---- Overall LDLR biosynthesis is below 70% of wild-type activity. PS4_Moderate, PP4: Variant meets PM2 and is identified in at least 6 unrelated index cases who fulfill criteria for FH (1 case from PMID 16250003 (Fouchier SW et al., 2005); 2 cases with MedPed and Simon Broome criteria from Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation, Czech Republic, and PMID 22698793 (Tichý L et al., 2012); 2 cases meeting Simon Broome and DLCN criteria from Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière, France; 1 case with DLCN score>=6 from Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA, Australia). LINK:https://erepo.genome.network/evrepo/ui/classification/CA023717/MONDO:0007750/013

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000013 ( 0 hom. )

Consequence

LDLR
NM_000527.5 missense

Scores

7
4
8

Clinical Significance

Likely pathogenic reviewed by expert panel P:9U:7B:1O:1

Conservation

PhyloP100: 1.85
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]

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

PS3
For more information check the summary or visit ClinGen Evidence Repository.
PS4
For more information check the summary or visit ClinGen Evidence Repository.
PM1
For more information check the summary or visit ClinGen Evidence Repository.
PM2
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
LDLRNM_000527.5 linkuse as main transcriptc.542C>G p.Pro181Arg missense_variant 4/18 ENST00000558518.6 NP_000518.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
LDLRENST00000558518.6 linkuse as main transcriptc.542C>G p.Pro181Arg missense_variant 4/181 NM_000527.5 ENSP00000454071 P3P01130-1

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152204
Hom.:
0
Cov.:
33
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:
6
AN:
251308
Hom.:
0
AF XY:
0.0000368
AC XY:
5
AN XY:
135892
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:
0.0000528
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000130
AC:
19
AN:
1461720
Hom.:
0
Cov.:
33
AF XY:
0.0000151
AC XY:
11
AN XY:
727174
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:
0.0000171
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152204
Hom.:
0
Cov.:
33
AF XY:
0.0000134
AC XY:
1
AN XY:
74354
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
Alfa
AF:
0.0000282
Hom.:
0
Bravo
AF:
0.0000151
ExAC
AF:
0.0000494
AC:
6
EpiCase
AF:
0.000109
EpiControl
AF:
0.000178

ClinVar

Significance: Likely pathogenic
Submissions summary: Pathogenic:9Uncertain:7Benign:1Other:1
Revision: reviewed by expert panel
LINK: link

Submissions by phenotype

Hypercholesterolemia, familial, 1 Pathogenic:7Uncertain:2Benign:1
Likely pathogenic, criteria provided, single submitterclinical testingHuman Genome Sequencing Center Clinical Lab, Baylor College of MedicineApr 25, 2018This c.542C>G (p.Pro181Arg) variant in the LDLR gene has been reported in multiple familial hypercholesterolaemia patients [PMID: 11600564, 11754108, 16250003, 23375686] than that observed as extremely low in general population according to gnomad database. Functional studies showed impairment of precursor LDLR with reduced penetrance associated with this variant [PMID: 21868016]. Multiple in silico predictions suggest this proline to arginine is deleterious. Based upon above evidences, c.542C>G (p.Pro181Arg) variant in the LDLR gene is classified as likely pathogenic. -
Likely pathogenic, criteria provided, single submitterliterature onlyLDLR-LOVD, British Heart FoundationMar 25, 2016- -
Pathogenic, no assertion criteria providedresearchLaboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum-- -
Likely pathogenic, criteria provided, single submitterclinical testingLaboratory of molecular diagnosis of dyslipidemias, Università egli studi di Napoli Federico IIMay 24, 2021- -
Likely pathogenic, criteria provided, single submitterclinical testingU4M - Lille University & CHRU Lille, Université de Lille - CHRU de LilleMar 30, 2017- -
Likely benign, flagged submissionclinical testingCentre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-FoixDec 16, 2016subject mutated among 2600 FH index cases screened = 1 / Software predictions: Conflicting -
Uncertain significance, no assertion criteria providedclinical testingZotz-Klimas Genetics Lab, MVZ Zotz KlimasOct 09, 2023- -
Uncertain significance, criteria provided, single submitterclinical testingMolecular Genetics Laboratory, Centre for Cardiovascular Surgery and TransplantationNov 05, 2016- -
Likely pathogenic, criteria provided, single submitterclinical testingInstitute of Human Genetics, University of Leipzig Medical CenterSep 10, 2024Criteria applied: PS4_MOD,PM1,PM2,PM5,PP3 -
Likely pathogenic, reviewed by expert panelcurationClinGen Familial Hypercholesterolemia Variant Curation Expert PanelFeb 23, 2024The NM_000527.5(LDLR):c.542C>G (p.Pro181Arg) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM1, PM2, PS3_Moderate, PS4_Moderate and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 23 February 2024. The supporting evidence is as follows: PM2: PopMax MAF = 0.00005 (0.005%) in European (Non-Finnish) exomes+genomes (gnomAD v4.0.0). PM1: Variant meets PM2 and is a missense in exon 4. PS3_Moderate: Level 2 assay: PMID 21868016 (Garcia-Garcia A et al., 2011): COS-7 cells. Mature/precursor LDLR forms ratio ~60% ---- Overall LDLR biosynthesis is below 70% of wild-type activity. PS4_Moderate, PP4: Variant meets PM2 and is identified in at least 6 unrelated index cases who fulfill criteria for FH (1 case from PMID 16250003 (Fouchier SW et al., 2005); 2 cases with MedPed and Simon Broome criteria from Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation, Czech Republic, and PMID 22698793 (Tichý L et al., 2012); 2 cases meeting Simon Broome and DLCN criteria from Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière, France; 1 case with DLCN score>=6 from Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA, Australia). -
Familial hypercholesterolemia Pathogenic:2Uncertain:1
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpDec 07, 2023This sequence change replaces proline, which is neutral and non-polar, with arginine, which is basic and polar, at codon 181 of the LDLR protein (p.Pro181Arg). This variant is present in population databases (rs557344672, gnomAD 0.005%). This missense change has been observed in individuals with clinical features of familial hypercholesterolemia (PMID: 11754108, 16250003, 20045108, 21868016, 22698793; Invitae). This variant is also known as P160R. ClinVar contains an entry for this variant (Variation ID: 183089). 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 have shown that this missense change does not substantially affect LDLR function (PMID: 21868016, 25647241). For these reasons, this variant has been classified as Pathogenic. -
Uncertain significance, no assertion criteria providedclinical testingNatera, Inc.Sep 16, 2020- -
Likely pathogenic, criteria provided, single submitterclinical testingColor Diagnostics, LLC DBA Color HealthAug 10, 2023This missense variant replaces proline with arginine at codon 181 of the LDLR protein. This variant is also known as p.Pro160Arg in the mature protein. This variant alters a conserved proline residue in the LDLR type A repeat 4 ligand binding domain of the LDLR protein (a.a. 146-186), where pathogenic missense variants are found enriched (ClinVar-LDLR). Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown that the variant interfered with LDLR precursor processing to the mature form, although the mature mutant protein exhibited wild-type like LDLR activity (PMID: 21868016, 25647241). This variant has been reported in at least ten individuals affected with familial hypercholesterolemia (PMID: 11668640, 11754108, 20045108, 21310417, 21868016, 22698793, 23375686, 32977124; ClinVar SCV000503179.1, SCV000583701.1, SCV000540742.1). It has also been reported in three individuals affected with early-onset myocardial infarction (PMID: 25647241). This variant has been identified in 6/251308 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on available evidence, this variant is classified as Likely Pathogenic. -
not provided Uncertain:2Other:1
not provided, no classification providedin vitroDept. of Genetics and Pharmacogenomics, Merck Research Labs-- -
Uncertain significance, criteria provided, single submitterclinical testingGeneDxMay 24, 2024Not 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; Functional studies demonstrated that p.(P181R) is associated with altered LDLR precursor processing; however, it does not result in altered receptor activity (PMID: 21868016); Also known as p.(P160R); This variant is associated with the following publications: (PMID: 16250003, 21310417, 14508510, 20045108, 23375686, 11524740, 25487149, 22698793, 11754108, 11600564, 18279815, 25647241, 21868016, 31447099, 37409534, 35913489, 32977124) -
Uncertain significance, criteria provided, single submitterclinical testingQuest Diagnostics Nichols Institute San Juan CapistranoJul 24, 2020- -
not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpMar 01, 2024Variant summary: LDLR c.542C>G (p.Pro181Arg) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.7e-05 in 261608 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.542C>G has been reported in many FH patients/families with both co-segregation of variant with disease as well as lack of co-segregation observed (example, Garcia-Garcia_ 2001 and Garcia-Garcia _2011). In vitro functional studies showed that variant of interest altered LDLR precursor processing to the mature form, however, the protein activity was normal (Garcia-Garcia _2011) and showed comparable levels of cellular LDL-uptake to wild type (Thormaehlen_2015), suggesting a possible lack of functional effect which needs to be further clarified. The following publications have been ascertained in the context of this evaluation (PMID: 23375686, 16627557, 34297352, 25487149, 21310417, 18279815, 16250003, 21868016, 11668640, 11754108, 14508510, 20045108, 35913489, 25647241, 22698793, 31447099). ClinVar contains an entry for this variant (Variation ID: 183089). Based on the evidence outlined above, the variant was classified as uncertain significance. -
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsNov 15, 2018The p.P181R variant (also known as c.542C>G), located in coding exon 4 of the LDLR gene, results from a C to G substitution at nucleotide position 542. The proline at codon 181 is replaced by arginine, an amino acid with dissimilar properties. This variant (also described as p.P160R) has been reported in multiple individuals with familial hypercholesterolemia (FH) from a variety of ethnic backgrounds (Chaves FJ et al. J. Clin. Endocrinol. Metab., 2001 Oct;86:4926-32; Kuhrová V et al. Hum. Mutat., 2002 Jan;19:80; Fouchier SW et al. Hum. Mutat., 2005 Dec;26:550-6). In one family with FH, this variant was reported in an asymptomatic proband, as well as in her affected mother and her affected maternal aunt, but was not detected in a second affected maternal aunt (Garcia-Garcia AB et al. Atherosclerosis, 2011 Oct;218:423-30). This variant was also detected in three early onset myocardial infarction (MI) cases and in one non-MI control, but only one of these individuals was reported to have elevated LDL-C levels (Thormaehlen AS et al. PLoS Genet., 2015 Feb;11:e1004855). One functional study suggested this variant affects LDLR processing; however, LDLR activity did not appear to be impacted, and additional in vitro studies showed no significant change in LDL uptake (Garcia-Garcia AB et al. Atherosclerosis, 2011 Oct;218:423-30; Thormaehlen AS et al. PLoS Genet., 2015 Feb;11:e1004855). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is conflicting at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.17
BayesDel_addAF
Pathogenic
0.27
D
BayesDel_noAF
Pathogenic
0.31
CADD
Benign
22
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.84
D;.;.;.
Eigen
Uncertain
0.23
Eigen_PC
Benign
0.14
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Benign
0.85
T;D;D;D
M_CAP
Pathogenic
0.76
D
MetaRNN
Pathogenic
0.97
D;D;D;D
MetaSVM
Uncertain
0.56
D
MutationAssessor
Benign
1.4
L;.;.;L
MutationTaster
Benign
1.0
D;D;D;D;D;D;D
PrimateAI
Benign
0.37
T
PROVEAN
Uncertain
-4.2
D;D;D;D
REVEL
Pathogenic
0.71
Sift
Benign
0.34
T;T;T;T
Sift4G
Benign
0.15
T;T;T;T
Polyphen
0.99
D;.;.;.
Vest4
0.65
MutPred
0.78
Loss of phosphorylation at S177 (P = 0.1618);Loss of phosphorylation at S177 (P = 0.1618);.;Loss of phosphorylation at S177 (P = 0.1618);
MVP
1.0
MPC
0.80
ClinPred
0.83
D
GERP RS
4.3
Varity_R
0.52
gMVP
0.97

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.

Other links and lift over

dbSNP: rs557344672; hg19: chr19-11216124; API