rs149227308

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PM5PP5_Moderate

The NM_000527.5(LDLR):​c.1166C>A​(p.Thr389Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T389M) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 31)

Consequence

LDLR
NM_000527.5 missense

Scores

8
4
7

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 3.19
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 Likely_pathogenic. Variant got 6 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr19-11111619-C-T is described in Lovd as [Likely_pathogenic].
PP5
Variant 19-11111619-C-A is Pathogenic according to our data. Variant chr19-11111619-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2118340.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
LDLRNM_000527.5 linkc.1166C>A p.Thr389Lys missense_variant Exon 8 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.1166C>A p.Thr389Lys missense_variant Exon 8 of 18 1 NM_000527.5 ENSP00000454071.1 P01130-1

Frequencies

GnomAD3 genomes
Cov.:
31
GnomAD4 exome
Cov.:
32
GnomAD4 genome
Cov.:
31

ClinVar

Significance: Likely pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Familial hypercholesterolemia Pathogenic:1
Nov 29, 2022
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces threonine, which is neutral and polar, with lysine, which is basic and polar, at codon 389 of the LDLR protein (p.Thr389Lys). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with LDLR-related conditions. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt LDLR protein function. This variant disrupts the p.Thr389 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 17196209, 23375686; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.18
BayesDel_addAF
Pathogenic
0.29
D
BayesDel_noAF
Pathogenic
0.18
CADD
Benign
22
DANN
Uncertain
0.99
DEOGEN2
Pathogenic
0.83
D;.;.;.;.;.
Eigen
Benign
-0.15
Eigen_PC
Benign
-0.089
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Benign
0.80
T;T;T;T;T;T
M_CAP
Pathogenic
0.56
D
MetaRNN
Uncertain
0.70
D;D;D;D;D;D
MetaSVM
Pathogenic
0.85
D
MutationAssessor
Benign
-1.0
N;.;.;.;.;N
PrimateAI
Benign
0.45
T
PROVEAN
Pathogenic
-4.5
D;D;D;D;D;D
REVEL
Pathogenic
0.68
Sift
Uncertain
0.0020
D;T;D;D;D;D
Sift4G
Uncertain
0.012
D;D;D;D;D;D
Polyphen
0.98
D;.;.;.;.;.
Vest4
0.48
MutPred
0.56
Gain of ubiquitination at T389 (P = 0.0238);Gain of ubiquitination at T389 (P = 0.0238);.;.;.;Gain of ubiquitination at T389 (P = 0.0238);
MVP
1.0
MPC
0.84
ClinPred
0.90
D
GERP RS
4.5
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.79
gMVP
0.95

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-11222295; API