rs13306505

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_000527.5(LDLR):​c.2579C>A​(p.Ala860Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,182 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Consequence

LDLR
NM_000527.5 missense

Scores

2
10
7

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.51
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
LDLRNM_000527.5 linkuse as main transcriptc.2579C>A p.Ala860Glu missense_variant 18/18 ENST00000558518.6 NP_000518.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
LDLRENST00000558518.6 linkuse as main transcriptc.2579C>A p.Ala860Glu missense_variant 18/181 NM_000527.5 ENSP00000454071 P3P01130-1

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152182
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
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:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD4 exome
Cov.:
34
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152182
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
74336
show subpopulations
Gnomad4 AFR
AF:
0.00
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:
0.0000147
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.095
BayesDel_addAF
Pathogenic
0.20
D
BayesDel_noAF
Uncertain
0.050
CADD
Benign
22
DANN
Uncertain
0.99
DEOGEN2
Uncertain
0.57
D;.;.;.;.
Eigen
Benign
-0.011
Eigen_PC
Benign
-0.17
FATHMM_MKL
Benign
0.52
D
LIST_S2
Benign
0.81
T;T;T;T;T
M_CAP
Pathogenic
0.56
D
MetaRNN
Uncertain
0.59
D;D;D;D;D
MetaSVM
Uncertain
0.15
D
MutationAssessor
Uncertain
2.8
M;.;.;.;.
MutationTaster
Benign
1.0
N;N;N;N;N;N;N
PrimateAI
Uncertain
0.49
T
PROVEAN
Benign
-2.0
N;N;N;N;N
REVEL
Uncertain
0.51
Sift
Uncertain
0.0010
D;D;D;D;D
Sift4G
Uncertain
0.0030
D;D;D;D;D
Polyphen
1.0
D;.;.;.;.
Vest4
0.36
MutPred
0.38
Gain of solvent accessibility (P = 0.0456);.;.;.;.;
MVP
0.95
MPC
0.84
ClinPred
0.95
D
GERP RS
2.6
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.45
gMVP
0.90

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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: rs13306505; hg19: chr19-11241988; API