rs749780672
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2PP3_StrongPP5
The NM_000527.5(LDLR):c.1335C>A(p.Asp445Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000118 in 1,613,858 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 29)
Exomes 𝑓: 0.000012 ( 1 hom. )
Consequence
LDLR
NM_000527.5 missense
NM_000527.5 missense
Scores
10
8
1
Clinical Significance
Conservation
PhyloP100: 0.229
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 9 ACMG points.
PM1
In a strand (size 5) in uniprot entity LDLR_HUMAN there are 16 pathogenic changes around while only 0 benign (100%) in NM_000527.5
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.986
PP5
Variant 19-11113426-C-A is Pathogenic according to our data. Variant chr19-11113426-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 251794.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Pathogenic=1, Likely_pathogenic=1}. Variant chr19-11113426-C-A is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
LDLR | NM_000527.5 | c.1335C>A | p.Asp445Glu | missense_variant | 9/18 | ENST00000558518.6 | NP_000518.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
LDLR | ENST00000558518.6 | c.1335C>A | p.Asp445Glu | missense_variant | 9/18 | 1 | NM_000527.5 | ENSP00000454071.1 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152160Hom.: 0 Cov.: 29
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GnomAD3 exomes AF: 0.0000159 AC: 4AN: 251246Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135856
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GnomAD4 exome AF: 0.0000123 AC: 18AN: 1461698Hom.: 1 Cov.: 33 AF XY: 0.0000138 AC XY: 10AN XY: 727144
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GnomAD4 genome AF: 0.00000657 AC: 1AN: 152160Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0AN XY: 74318
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:2Uncertain:2
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Hypercholesterolemia, familial, 1 Pathogenic:1Uncertain:1
Likely pathogenic, criteria provided, single submitter | literature only | LDLR-LOVD, British Heart Foundation | Mar 25, 2016 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Dec 18, 2023 | This missense variant replaces aspartic acid with glutamic acid at codon 445 of the LDLR protein. This variant is also known as pAsp424Glu in the mature protein, and as FH-Finn-8 in the literature. This variant alters a conserved aspartic acid residue in the LDLR type B repeat 2 of the LDLR protein (a.a. 439 - 485), where pathogenic missense variants are found enriched (ClinVar-LDLR). Computational prediction tools indicate that this variant has a deleterious impact on protein structure and function. One functional study suggested this variant does not affect protein expression, folding, or intracellular trafficking (PMID: 31587492). This variant has been reported in three individuals affected with familial hypercholesterolemia (PMID: 7573037, 15199436, 33740630, 35474963; DOI: 10.1093/eurheartj/ehab724.2566). This variant has been identified in 4/251246 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jun 09, 2023 | Located in the conserved YWTD_ motif in a region that is predicted to form a beta-propeller structure (Springer, 1998); the beta propeller and three EGF-like modules constitute the EGF precursor homology domain which is is critical for ligand release and recycling of the receptor (Rudenko et al., 2002; Davis et al., 1987).; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 11373616, 15199436, 31587492, 7573037, 33740630, 33955087, 12459547, 3494949) - |
Familial hypercholesterolemia Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Nov 26, 2023 | This missense variant replaces aspartic acid with glutamic acid at codon 445 of the LDLR protein. This variant is also known as pAsp424Glu in the mature protein, and as FH-Finn-8 in the literature. This variant alters a conserved aspartic acid residue in the LDLR type B repeat 2 of the LDLR protein (a.a. 439 - 485), where pathogenic missense variants are found enriched (ClinVar-LDLR). Computational prediction tools indicate that this variant has a deleterious impact on protein structure and function. One functional study suggested this variant does not affect protein expression, folding, or intracellular trafficking (PMID: 31587492). This variant has been reported in three individuals affected with familial hypercholesterolemia (PMID: 7573037, 15199436, 33740630, 35474963; DOI: 10.1093/eurheartj/ehab724.2566). This variant has been identified in 4/251246 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Benign
DANN
Uncertain
DEOGEN2
Pathogenic
D;.;.;.;.;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D;D;D;D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
M;.;.;.;.;M
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;D;D;D;D;D
REVEL
Pathogenic
Sift
Pathogenic
D;D;D;D;D;D
Sift4G
Uncertain
D;D;D;D;D;D
Polyphen
P;.;.;.;.;.
Vest4
MutPred
Loss of sheet (P = 0.1398);Loss of sheet (P = 0.1398);.;.;.;Loss of sheet (P = 0.1398);
MVP
MPC
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at