NM_000527.5:c.2384C>A

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 9P and 1B. PM1PM2PP2PP3_StrongBP6

The NM_000527.5(LDLR):​c.2384C>A​(p.Pro795His) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,760 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. P795R) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 31)
Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

LDLR
NM_000527.5 missense

Scores

9
8
2

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: 3.86

Publications

1 publications found
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]
LDLR Gene-Disease associations (from GenCC):
  • hypercholesterolemia, familial, 1
    Inheritance: AD, SD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, ClinGen
  • homozygous familial hypercholesterolemia
    Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

PM1
In a hotspot region, there are 4 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;
PP2
Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 678 curated pathogenic missense variants (we use a threshold of 10). The gene has 92 curated benign missense variants. Gene score misZ: 0.12407 (below the threshold of 3.09). Trascript score misZ: 0.59338 (below the threshold of 3.09). GenCC associations: The gene is linked to hypercholesterolemia, familial, 1, homozygous familial hypercholesterolemia.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.984
BP6
Variant 19-11128080-C-A is Benign according to our data. Variant chr19-11128080-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 252296.We mark this variant Likely_benign, oryginal submission is: [Conflicting_classifications_of_pathogenicity].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
LDLRNM_000527.5 linkc.2384C>A p.Pro795His missense_variant Exon 16 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.2384C>A p.Pro795His missense_variant Exon 16 of 18 1 NM_000527.5 ENSP00000454071.1 P01130-1

Frequencies

GnomAD3 genomes
Cov.:
31
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461760
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
727178
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33480
American (AMR)
AF:
0.00
AC:
0
AN:
44724
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26134
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39698
South Asian (SAS)
AF:
0.00
AC:
0
AN:
86256
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53394
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5766
European-Non Finnish (NFE)
AF:
8.99e-7
AC:
1
AN:
1111922
Other (OTH)
AF:
0.00
AC:
0
AN:
60386
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.625
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
GnomAD4 genome
Cov.:
31
Alfa
AF:
0.00
Hom.:
0

ClinVar

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

Submissions by phenotype

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

- -

Mar 01, 2016
Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:curation;literature only

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.80
BayesDel_addAF
Pathogenic
0.42
D
BayesDel_noAF
Pathogenic
0.37
CADD
Uncertain
24
DANN
Uncertain
0.99
DEOGEN2
Pathogenic
0.93
D;.;.;.;.;.
Eigen
Uncertain
0.36
Eigen_PC
Benign
0.21
FATHMM_MKL
Uncertain
0.94
D
LIST_S2
Uncertain
0.86
D;T;D;D;T;D
M_CAP
Pathogenic
0.63
D
MetaRNN
Pathogenic
0.98
D;D;D;D;D;D
MetaSVM
Pathogenic
0.84
D
MutationAssessor
Uncertain
2.4
M;.;.;.;.;M
PhyloP100
3.9
PrimateAI
Uncertain
0.58
T
PROVEAN
Pathogenic
-8.3
D;D;D;D;D;D
REVEL
Pathogenic
0.73
Sift
Uncertain
0.0010
D;D;D;D;D;D
Sift4G
Uncertain
0.016
D;D;D;D;D;D
Polyphen
1.0
D;.;.;.;.;.
Vest4
0.75
MutPred
0.85
Gain of helix (P = 0.0854);Gain of helix (P = 0.0854);.;.;.;Gain of helix (P = 0.0854);
MVP
1.0
MPC
0.87
ClinPred
0.99
D
GERP RS
4.9
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.59
gMVP
0.93
Mutation Taster
=7/93
disease causing

Splicing

Name
Calibrated prediction
Score
Prediction
Splicevardb
2.0
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

Other links and lift over

dbSNP: rs879255184; hg19: chr19-11238756; API