chr19-11120502-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PS4_SupportingPM2PP3PP4

This summary comes from the ClinGen Evidence Repository: NM_000527.5(LDLR):c.2120A>T (p.Asp707Val) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes PM2, PP3, PP4 and PS4_Supporting 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 v2.1.1).PP3: REVEL = 0.964. PS4_Supporting, PP4: Variant meets PM2 and is identified in at least 3 unrelated index cases who fulfill criteria for FH, after alternative causes of high cholesterol were excluded (2 cases with DLCN score >=6 from the 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 Robarts Research Institute, Canada). LINK:https://erepo.genome.network/evrepo/ui/classification/CA10585780/MONDO:0007750/013

Frequency

Genomes: not found (cov: 32)

Consequence

LDLR
NM_000527.5 missense

Scores

15
2
2

Clinical Significance

Uncertain significance reviewed by expert panel P:7U:1

Conservation

PhyloP100: 7.27
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 Uncertain_significance. Variant got 5 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.
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 rank MANE Protein UniProt
LDLRNM_000527.5 linkc.2120A>T p.Asp707Val missense_variant Exon 14 of 18 ENST00000558518.6 NP_000518.1 P01130-1A0A024R7D5

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
LDLRENST00000558518.6 linkc.2120A>T p.Asp707Val missense_variant Exon 14 of 18 1 NM_000527.5 ENSP00000454071.1 P01130-1

Frequencies

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

ClinVar

Significance: Uncertain significance
Submissions summary: Pathogenic:7Uncertain:1
Revision: reviewed by expert panel
LINK: link

Submissions by phenotype

Hypercholesterolemia, familial, 1 Pathogenic:4Uncertain:1
Uncertain significance, reviewed by expert panelcurationClinGen Familial Hypercholesterolemia Variant Curation Expert PanelFeb 23, 2024NM_000527.5(LDLR):c.2120A>T (p.Asp707Val) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes PM2, PP3, PP4 and PS4_Supporting 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 v2.1.1). PP3: REVEL = 0.964. PS4_Supporting, PP4: Variant meets PM2 and is identified in at least 3 unrelated index cases who fulfill criteria for FH, after alternative causes of high cholesterol were excluded (2 cases with DLCN score >=6 from the 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 Robarts Research Institute, Canada). -
Likely pathogenic, criteria provided, single submitterclinical testingRobarts Research Institute, Western University-- -
Likely pathogenic, criteria provided, single submitterliterature onlyLDLR-LOVD, British Heart FoundationMar 25, 2016- -
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/software prediction damaging -
Likely pathogenic, no assertion criteria providedresearchdeCODE genetics, AmgenJul 21, 2023The variant NM_000527.5:c.2120A>T (chr19:11120502) in LDLR was detected in 3 heterozygotes out of 58K WGS Icelanders (MAF= 0,003%). Following imputation in a set of 166K Icelanders (4 imputed heterozygotes) we observed an association with LDL cholesterol using measurements from 128289 individuals (Effect (SD)= 2.53, P= 8.17e-06), Non-HDL cholesterol using measurements from 136901 individuals (Effect (SD)= 2.31, P= 3.79e-05), pure hypercholesterolaemia using 1515 cases and 283197 controls (OR= 84.06, P= 3.36e-04) and myocardial infarction using 25692 cases and 320832 controls (OR= 56.16, P= 1.36e-03). This variant has been reported in ClinVar previously as likely pathogenic. Based on ACMG criteria (PS4, PM1, PP3, PP5_Strong) this variant classifies as likely pathogenic. -
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingGeneDxSep 08, 2017A variant that is likely pathogenic was identified in the LDLR gene. The D707V variant has been reported in association with FH (Marduel et al., 2010; Wang et al., 2016). The D707V variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The D707V variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Finally, while missense variants in the same residue (D707N, D707Y) have been reported in the Human Gene Mutation Database in association with FH (Stenson et al., 2014), the pathogenicity of these variants has not been definitively determined. -
Cardiovascular phenotype Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingAmbry GeneticsMay 30, 2024The p.D707V variant (also known as c.2120A>T), located in coding exon 14 of the LDLR gene, results from an A to T substitution at nucleotide position 2120. The aspartic acid at codon 707 is replaced by valine, an amino acid with highly dissimilar properties. This variant has been reported in individuals with familial hypercholesterolemia (FH) (Marduel M et al. Hum Mutat, 2010 Nov;31:E1811-24; Wang J et al. Arterioscler Thromb Vasc Biol, 2016 Dec;36:2439-2445; Björnsson E et al. Arterioscler Thromb Vasc Biol, 2021 Oct;41:2616-2628). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic. -
Familial hypercholesterolemia Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingHuman Genome Sequencing Center Clinical Lab, Baylor College of MedicineOct 30, 2019The c.2120A>T (p.Asp707Val) variant in the LDLR gene has been reported in individuals with familial hypercholesterolemia (FH) (PMID: 20809525, 27765764) and is absent from general population databases. Multiple lines of in silico algorithms have predicted this p.Asp707Val change to be deleterious. In addition, missense variants in the same amino acid residue (p.Asp707Asn and p.Asp707Tyr) have also been reported in affected individuals with FH (PMID: 22881376, 19318025). Therefore, this c.2120A>T (p.Asp707Val) variant in the LDLR gene is classified as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.96
BayesDel_addAF
Pathogenic
0.57
D
BayesDel_noAF
Pathogenic
0.59
CADD
Pathogenic
29
DANN
Uncertain
0.99
DEOGEN2
Pathogenic
0.95
D;.;.;.;.
Eigen
Pathogenic
0.91
Eigen_PC
Pathogenic
0.79
FATHMM_MKL
Pathogenic
1.0
D
LIST_S2
Uncertain
0.95
D;D;D;D;D
M_CAP
Pathogenic
0.96
D
MetaRNN
Pathogenic
0.98
D;D;D;D;D
MetaSVM
Pathogenic
0.96
D
MutationAssessor
Pathogenic
4.3
H;.;.;.;H
PrimateAI
Benign
0.44
T
PROVEAN
Pathogenic
-7.6
D;D;D;D;D
REVEL
Pathogenic
0.96
Sift
Pathogenic
0.0
D;D;D;D;D
Sift4G
Pathogenic
0.0
D;D;D;D;D
Polyphen
0.97
D;.;.;.;.
Vest4
0.89
MutPred
0.76
Loss of disorder (P = 0.0447);Loss of disorder (P = 0.0447);.;.;Loss of disorder (P = 0.0447);
MVP
1.0
MPC
0.95
ClinPred
1.0
D
GERP RS
5.3
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.9
Varity_R
0.97
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: rs879255143; hg19: chr19-11231178; API