chr19-11123188-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PM1PM2BP4_ModerateBP6_Moderate

The NM_000527.5(LDLR):​c.2155G>C​(p.Val719Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: not found (cov: 30)

Consequence

LDLR
NM_000527.5 missense

Scores

3
16

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.238
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 0 ACMG points.

PM1
In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 10 uncertain in NM_000527.5
PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.2548041).
BP6
Variant 19-11123188-G-C is Benign according to our data. Variant chr19-11123188-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 252243.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-11123188-G-C is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
LDLRNM_000527.5 linkuse as main transcriptc.2155G>C p.Val719Leu missense_variant 15/18 ENST00000558518.6

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
LDLRENST00000558518.6 linkuse as main transcriptc.2155G>C p.Val719Leu missense_variant 15/181 NM_000527.5 P3P01130-1

Frequencies

GnomAD3 genomes
Cov.:
30
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
30

ClinVar

Significance: Likely benign
Submissions summary: Benign:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Hypercholesterolemia, familial, 1 Benign:1
Likely benign, criteria provided, single submitterliterature onlyLDLR-LOVD, British Heart FoundationMar 25, 2016- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.096
BayesDel_addAF
Uncertain
0.088
D
BayesDel_noAF
Benign
-0.11
CADD
Benign
1.1
DANN
Benign
0.49
DEOGEN2
Benign
0.36
T;.;.;.;.;.
Eigen
Benign
-1.3
Eigen_PC
Benign
-1.4
FATHMM_MKL
Benign
0.11
N
LIST_S2
Benign
0.56
T;T;T;T;T;T
M_CAP
Uncertain
0.17
D
MetaRNN
Benign
0.25
T;T;T;T;T;T
MetaSVM
Benign
-0.62
T
MutationAssessor
Benign
0.69
N;.;.;.;.;N
MutationTaster
Benign
1.0
N;N;N;N;N;N;N
PrimateAI
Benign
0.28
T
PROVEAN
Benign
-0.67
N;N;N;N;N;N
REVEL
Uncertain
0.51
Sift
Benign
0.81
T;T;T;T;T;T
Sift4G
Benign
0.73
T;T;T;T;T;T
Polyphen
0.0
B;.;.;.;.;.
Vest4
0.35
MutPred
0.73
Loss of sheet (P = 0.0315);Loss of sheet (P = 0.0315);.;.;.;Loss of sheet (P = 0.0315);
MVP
0.95
MPC
0.21
ClinPred
0.047
T
GERP RS
-1.3
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.039
gMVP
0.64

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: rs879255151; hg19: chr19-11233864; API