rs879254921

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PS4_ModeratePP1_ModeratePM2PP4PP3

This summary comes from the ClinGen Evidence Repository: The NM_000527.5(LDLR):c.1495T>C (p.Ser499Pro) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2, PS4_Moderate, PP1_Moderate, PP3 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: This variant is absent from gnomAD (gnomAD v4.0.0).PP3: REVEL = 0.758. PS4_Moderate, PP4: Variant meets PM2 and is identified in at least 6 unrelated index cases who fulfill criteria for FH (4 cases with DLCN score >=6 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; 2 cases with possible FH by Simon Broome criteria from Service de Biochimie et de Biologie Moléculaire, Hospices Civils de Lyon, France). PP1_Moderate - Variant segregates with FH phenotype in 4 informative meiosis in 4 families from different labs (Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière, France; Service de Biochimie de Biologie Moléculaire, Hospices Civils de Lyon, France): 4 affected family members have the variant. LINK:https://erepo.genome.network/evrepo/ui/classification/CA10585480/MONDO:0007750/013

Frequency

Genomes: not found (cov: 32)

Consequence

LDLR
ENST00000558518.6 missense

Scores

10
5
4

Clinical Significance

Likely pathogenic reviewed by expert panel P:5B:1

Conservation

PhyloP100: 6.08
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 8 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.
PP1
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
LDLRNM_000527.5 linkuse as main transcriptc.1495T>C p.Ser499Pro missense_variant 10/18 ENST00000558518.6 NP_000518.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
LDLRENST00000558518.6 linkuse as main transcriptc.1495T>C p.Ser499Pro missense_variant 10/181 NM_000527.5 ENSP00000454071 P3P01130-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
35
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Likely pathogenic
Submissions summary: Pathogenic:5Benign:1
Revision: reviewed by expert panel
LINK: link

Submissions by phenotype

Hypercholesterolemia, familial, 1 Pathogenic:4Benign:1
Pathogenic, criteria provided, single submitterclinical testingU4M - Lille University & CHRU Lille, Université de Lille - CHRU de LilleMar 30, 2017- -
Likely pathogenic, criteria provided, single submitterclinical testingCentre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-FoixDec 16, 2016subjects mutated among 2600 FH index cases screened = 5 , family members = 3 with co-segregation/Software predictions: Conflicting -
Likely pathogenic, criteria provided, single submitterclinical testingMolecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute-- -
Likely benign, criteria provided, single submitterliterature onlyLDLR-LOVD, British Heart FoundationMar 25, 2016- -
Likely pathogenic, reviewed by expert panelcurationClinGen Familial Hypercholesterolemia Variant Curation Expert PanelFeb 23, 2024The NM_000527.5(LDLR):c.1495T>C (p.Ser499Pro) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2, PS4_Moderate, PP1_Moderate, PP3 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: This variant is absent from gnomAD (gnomAD v4.0.0). PP3: REVEL = 0.758. PS4_Moderate, PP4: Variant meets PM2 and is identified in at least 6 unrelated index cases who fulfill criteria for FH (4 cases with DLCN score >=6 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; 2 cases with possible FH by Simon Broome criteria from Service de Biochimie et de Biologie Moléculaire, Hospices Civils de Lyon, France). PP1_Moderate - Variant segregates with FH phenotype in 4 informative meiosis in 4 families from different labs (Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière, France; Service de Biochimie de Biologie Moléculaire, Hospices Civils de Lyon, France): 4 affected family members have the variant. -
Familial hypercholesterolemia Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpNov 29, 2022This variant is not present in population databases (gnomAD no frequency). This sequence change replaces serine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 499 of the LDLR protein (p.Ser499Pro). This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 12436241). 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. 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. ClinVar contains an entry for this variant (Variation ID: 251870). This variant is also known as S478P. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
1.0
BayesDel_addAF
Pathogenic
0.48
D
BayesDel_noAF
Pathogenic
0.45
CADD
Uncertain
23
DANN
Uncertain
0.99
DEOGEN2
Pathogenic
0.93
D;.;.;.;.;.
Eigen
Benign
-0.20
Eigen_PC
Benign
-0.21
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Benign
0.79
T;T;T;T;T;T
M_CAP
Pathogenic
0.79
D
MetaRNN
Pathogenic
0.99
D;D;D;D;D;D
MetaSVM
Uncertain
0.54
D
MutationAssessor
Pathogenic
2.9
M;.;.;.;.;M
MutationTaster
Benign
1.0
D;D;D;D;D;D;D
PrimateAI
Uncertain
0.56
T
PROVEAN
Pathogenic
-4.9
D;D;D;D;D;D
REVEL
Pathogenic
0.76
Sift
Uncertain
0.0020
D;D;D;D;D;D
Sift4G
Uncertain
0.0040
D;T;D;D;D;D
Polyphen
0.036
B;.;.;.;.;.
Vest4
0.90
MutPred
0.89
Loss of catalytic residue at S499 (P = 0.0465);Loss of catalytic residue at S499 (P = 0.0465);.;.;.;Loss of catalytic residue at S499 (P = 0.0465);
MVP
1.0
MPC
0.69
ClinPred
0.98
D
GERP RS
3.7
Varity_R
0.97
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.

Other links and lift over

dbSNP: rs879254921; hg19: chr19-11224347; API