19-11113376-G-C

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PP4PP3PS4_SupportingPM5PS3PM2

This summary comes from the ClinGen Evidence Repository: The NM_000527.5(LDLR):c.1285G>C (p.Val429Leu) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PS3, PM2, PM5, PP3, PP4 and PS4_Supporting, as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 27 March 2023.The supporting evidence is as follows:PM2: This variant is absent from gnomAD (gnomAD v2.1.1).PP3: REVEL = 0.764. PM5: There is 1 variant in the same codon classified as Pathogenic by these guidelines, NM_000527.5(LDLR): c.1285G=6 from PathWest Laboratory Medicine WA, Australia; 1 case with possible FH by Simon Broome criteria from Instituto Nacional de Saúde Dr. Ricardo Jorge, Portugal, PMID 17765246 (Bourbon et al., 2008). LINK:https://erepo.genome.network/evrepo/ui/classification/CA10576303/MONDO:0007750/013

Frequency

Genomes: not found (cov: 29)

Consequence

LDLR
NM_000527.5 missense

Scores

7
7
5

Clinical Significance

Pathogenic reviewed by expert panel P:3U:1

Conservation

PhyloP100: 2.72
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.
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.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
LDLRNM_000527.5 linkc.1285G>C p.Val429Leu missense_variant 9/18 ENST00000558518.6 NP_000518.1 P01130-1A0A024R7D5

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
LDLRENST00000558518.6 linkc.1285G>C p.Val429Leu missense_variant 9/181 NM_000527.5 ENSP00000454071.1 P01130-1

Frequencies

GnomAD3 genomes
Cov.:
29
GnomAD4 exome
Cov.:
32
GnomAD4 genome
Cov.:
29

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:3Uncertain:1
Revision: reviewed by expert panel
LINK: link

Submissions by phenotype

Hypercholesterolemia, familial, 1 Pathogenic:3Uncertain:1
Pathogenic, reviewed by expert panelcurationClinGen Familial Hypercholesterolemia Variant Curation Expert PanelMar 27, 2023The NM_000527.5(LDLR):c.1285G>C (p.Val429Leu) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PS3, PM2, PM5, PP3, PP4 and PS4_Supporting, as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 27 March 2023. The supporting evidence is as follows: PM2: This variant is absent from gnomAD (gnomAD v2.1.1). PP3: REVEL = 0.764. PM5: There is 1 variant in the same codon classified as Pathogenic by these guidelines, NM_000527.5(LDLR): c.1285G<A (p.Val429Met) (ClinVar ID: 3694). PS3: Level 1 assay: Heterologous cells (CHO), 125I-LDL and WB assays, 22% cell surface LDLR and binding and 10% uptake, PMID 25386756 (Etxebarria et al., 2014). Level 1 assay: Heterologous cells (CHO), 125I-LDL and WB assays, 15-30% LDLR activity, reduced mature protein, PMID 23021490 (Silva et al, 2012). ---- Overall, functional studies show an activity below 70% of wild-type, consistent with damaging effect. PS4_Supporting, PP4: Variant meets PM2 and is identified in at least 3 unrelated index cases (2 cases with DLCN score >=6 from PathWest Laboratory Medicine WA, Australia; 1 case with possible FH by Simon Broome criteria from Instituto Nacional de Saúde Dr. Ricardo Jorge, Portugal, PMID 17765246 (Bourbon et al., 2008). -
Uncertain significance, no assertion criteria providedclinical testingCardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley HospitalOct 04, 2013- -
Pathogenic, criteria provided, single submitterresearchCardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo JorgeMar 01, 20160/208 non-FH alleles -
Likely pathogenic, criteria provided, single submitterliterature onlyLDLR-LOVD, British Heart FoundationMar 25, 2016- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.81
BayesDel_addAF
Pathogenic
0.24
D
BayesDel_noAF
Uncertain
0.11
CADD
Uncertain
24
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.64
D;.;.;.;.;.
Eigen
Uncertain
0.33
Eigen_PC
Uncertain
0.36
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Benign
0.84
T;T;T;T;D;T
M_CAP
Pathogenic
0.59
D
MetaRNN
Pathogenic
0.93
D;D;D;D;D;D
MetaSVM
Pathogenic
0.88
D
MutationAssessor
Benign
1.7
L;.;.;.;.;L
PrimateAI
Uncertain
0.58
T
PROVEAN
Benign
-2.3
N;N;N;N;N;N
REVEL
Pathogenic
0.76
Sift
Uncertain
0.016
D;D;D;D;D;D
Sift4G
Benign
0.11
T;T;T;T;T;T
Polyphen
0.11
B;.;.;.;.;.
Vest4
0.51
MutPred
0.86
Loss of catalytic residue at R427 (P = 0.4366);Loss of catalytic residue at R427 (P = 0.4366);.;.;.;Loss of catalytic residue at R427 (P = 0.4366);
MVP
1.0
MPC
0.43
ClinPred
0.91
D
GERP RS
4.9
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.52
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: rs28942078; hg19: chr19-11224052; API