19-11116882-T-G

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PS3PP1_ModeratePM2PP3PP4PS4_Supporting

This summary comes from the ClinGen Evidence Repository: The NM_000527.5(LDLR):c.1729T>G (p.Trp577Gly) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying evidence codes PS3, PP1_moderate, PM2, PP3, PS4_supporting, 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: PS3: Level 1 assays: PMID 25378237: Heterologous cells, FACS assays -10-15% LDL-LDLR binding; 5% LDL-LDLR uptake; 5% cell surface LDLR---- activity is below 70% of wild-type, so functional study is consistent with damaging effect.PP1_moderate: Variant segregates with FH phenotype in at least 4 informative meiosis from 1 family from Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation)PM2: This variant is absent from gnomAD (gnomAD v2.1.1).PP3: REVEL = 0.937.PS4_supporting: Variant meets PM2 and is identified in 2 index cases (1 case with DLCN criteria>=6 from Robarts Research Institute; 1 case with DLCN criteria>=6 from Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation))PP4: Variant meets PM2 and is identified in 2 index cases who fulfill clinical criteria for FH from several labs (see PS4 for details), after alternative causes of high cholesterol were excluded. LINK:https://erepo.genome.network/evrepo/ui/classification/CA10585585/MONDO:0007750/013

Frequency

Genomes: not found (cov: 32)

Consequence

LDLR
NM_000527.5 missense

Scores

16
1
2

Clinical Significance

Pathogenic reviewed by expert panel P:7

Conservation

PhyloP100: 7.88
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 Pathogenic. Variant got 11 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.
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.1729T>G p.Trp577Gly missense_variant 12/18 ENST00000558518.6 NP_000518.1 P01130-1A0A024R7D5

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
LDLRENST00000558518.6 linkuse as main transcriptc.1729T>G p.Trp577Gly missense_variant 12/181 NM_000527.5 ENSP00000454071.1 P01130-1

Frequencies

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

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:7
Revision: reviewed by expert panel
LINK: link

Submissions by phenotype

Hypercholesterolemia, familial, 1 Pathogenic:6
Likely pathogenic, criteria provided, single submitterclinical testingRobarts Research Institute, Western University-- -
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, 2016subject mutated among 2600 FH index cases screened = 1 , family member = 1 with co-segregation / Other mutation at same codon/software prediction damaging -
Likely pathogenic, criteria provided, single submitterliterature onlyLDLR-LOVD, British Heart FoundationMar 25, 2016- -
Pathogenic, criteria provided, single submitterresearchFundacion Hipercolesterolemia FamiliarMar 01, 2016- -
Pathogenic, reviewed by expert panelcurationClinGen Familial Hypercholesterolemia Variant Curation Expert PanelApr 28, 2023The NM_000527.5(LDLR):c.1729T>G (p.Trp577Gly) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying evidence codes PS3, PP1_moderate, PM2, PP3, PS4_supporting, 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: PS3: Level 1 assays: PMID 25378237: Heterologous cells, FACS assays -10-15% LDL-LDLR binding; 5% LDL-LDLR uptake; 5% cell surface LDLR ---- activity is below 70% of wild-type, so functional study is consistent with damaging effect. PP1_moderate: Variant segregates with FH phenotype in at least 4 informative meiosis from 1 family from Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation) PM2: This variant is absent from gnomAD (gnomAD v2.1.1). PP3: REVEL = 0.937. PS4_supporting: Variant meets PM2 and is identified in 2 index cases (1 case with DLCN criteria>=6 from Robarts Research Institute; 1 case with DLCN criteria>=6 from Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation)) PP4: Variant meets PM2 and is identified in 2 index cases who fulfill clinical criteria for FH from several labs (see PS4 for details), after alternative causes of high cholesterol were excluded. -
Likely pathogenic, criteria provided, single submitterclinical testingMolecular Genetics Laboratory, Centre for Cardiovascular Surgery and TransplantationJan 22, 2017- -
Familial hypercholesterolemia Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingGENinCode PLCMay 17, 2024The c.1729T>G p.(Trp577Gly) missense variant in LDLR has been reported in 3 FH patients meeting clinical criteria, including a patient with a clinical diagnosis of FH after alternative causes of high cholesterol were excluded (PS4_SUPPORTING, PP4_ SUPPORTING; ClinGen FH VCEP and internal data). The variant has been reported to segregate with FH in 4 affected meioses (PP1_MODERATE; ClinGen FH VCEP data). This variant is absent from gnomAD v2.1.1 (PM2_MODERATE). This variant meets level 1 pathogenic functional study criteria with <70% of wild-type activity in expression/biosynthesis, LDL binding and LDL internalization (PS3_STRONG; PMID: 25378237) and has a REVEL score of 0.937 (PP3_SUPPORTING). Based on the evidence listed above, we have classified this variant as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.98
BayesDel_addAF
Pathogenic
0.58
D
BayesDel_noAF
Pathogenic
0.60
CADD
Pathogenic
29
DANN
Benign
0.97
DEOGEN2
Pathogenic
0.98
D;.;.;.;.;.
Eigen
Pathogenic
0.80
Eigen_PC
Pathogenic
0.67
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Pathogenic
1.0
D;D;D;D;D;D
M_CAP
Pathogenic
0.96
D
MetaRNN
Pathogenic
1.0
D;D;D;D;D;D
MetaSVM
Pathogenic
0.94
D
MutationAssessor
Pathogenic
4.1
H;.;.;.;.;H
PrimateAI
Uncertain
0.70
T
PROVEAN
Pathogenic
-13
D;D;D;D;D;D
REVEL
Pathogenic
0.94
Sift
Pathogenic
0.0
D;D;D;D;D;D
Sift4G
Pathogenic
0.0
D;D;D;D;D;D
Polyphen
1.0
D;.;.;.;.;.
Vest4
0.94
MutPred
0.95
Loss of catalytic residue at W577 (P = 0.0029);Loss of catalytic residue at W577 (P = 0.0029);.;.;.;Loss of catalytic residue at W577 (P = 0.0029);
MVP
1.0
MPC
1.1
ClinPred
1.0
D
GERP RS
5.5
Varity_R
0.99
gMVP
0.99

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: rs879255000; hg19: chr19-11227558; API