rs771917370

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1PM2PM5PP3_StrongPP5

The NM_000527.5(LDLR):​c.631C>G​(p.His211Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H211L) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 33)

Consequence

LDLR
NM_000527.5 missense

Scores

9
7
3

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:1

Conservation

PhyloP100: 7.78
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.

PM1
In a strand (size 3) in uniprot entity LDLR_HUMAN there are 8 pathogenic changes around while only 0 benign (100%) in NM_000527.5
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr19-11105538-A-T is described in Lovd as [Likely_pathogenic].
PP3
MetaRNN computational evidence supports a deleterious effect, 0.986
PP5
Variant 19-11105537-C-G is Pathogenic according to our data. Variant chr19-11105537-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 251334.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=1, Likely_pathogenic=1}.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
LDLRNM_000527.5 linkc.631C>G p.His211Asp missense_variant Exon 4 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.631C>G p.His211Asp missense_variant Exon 4 of 18 1 NM_000527.5 ENSP00000454071.1 P01130-1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
33
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:2Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Hypercholesterolemia, familial, 1 Pathogenic:1Uncertain:1
Mar 25, 2016
LDLR-LOVD, British Heart Foundation
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: literature only

- -

Mar 01, 2016
Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: research

0/190 non-FH alleles -

Familial hypercholesterolemia Pathogenic:1
Feb 10, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces histidine, which is basic and polar, with aspartic acid, which is acidic and polar, at codon 211 of the LDLR protein (p.His211Asp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with familial hypercholesterolemia (PMID: 17765246). ClinVar contains an entry for this variant (Variation ID: 251334). 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 with a positive predictive value of 95%. This variant disrupts the p.His211 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10570905, 17347910, 23064986, 27784735; 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
Uncertain
0.51
BayesDel_addAF
Pathogenic
0.49
D
BayesDel_noAF
Pathogenic
0.46
CADD
Uncertain
25
DANN
Uncertain
0.99
DEOGEN2
Pathogenic
0.86
D;.;.;.
Eigen
Uncertain
0.44
Eigen_PC
Uncertain
0.40
FATHMM_MKL
Pathogenic
1.0
D
LIST_S2
Benign
0.84
T;T;T;T
M_CAP
Pathogenic
0.47
D
MetaRNN
Pathogenic
0.99
D;D;D;D
MetaSVM
Pathogenic
0.92
D
MutationAssessor
Benign
0.87
L;.;.;L
PrimateAI
Uncertain
0.62
T
PROVEAN
Pathogenic
-7.4
D;D;D;D
REVEL
Pathogenic
0.89
Sift
Uncertain
0.013
D;D;D;D
Sift4G
Uncertain
0.0080
D;D;D;D
Polyphen
1.0
D;.;.;.
Vest4
0.79
MutPred
0.87
Gain of disorder (P = 0.0735);Gain of disorder (P = 0.0735);.;Gain of disorder (P = 0.0735);
MVP
1.0
MPC
0.95
ClinPred
0.99
D
GERP RS
5.6
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.8
Varity_R
0.85
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: rs771917370; hg19: chr19-11216213; API