rs879254713
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_000527.5(LDLR):c.901G>T(p.Asp301Tyr) variant causes a missense change. 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D301G) has been classified as Likely pathogenic.
Frequency
Genomes: not found (cov: 32)
Consequence
LDLR
NM_000527.5 missense
NM_000527.5 missense
Scores
14
2
2
Clinical Significance
Conservation
PhyloP100: 5.61
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 18 ACMG points.
PM1
?
In a hotspot region, there are 12 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 11 uncertain 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 chr19-11107476-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 251514.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.995
PP5
?
Variant 19-11107475-G-T is Pathogenic according to our data. Variant chr19-11107475-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 251512.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-11107475-G-T is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
LDLR | NM_000527.5 | c.901G>T | p.Asp301Tyr | missense_variant | 6/18 | ENST00000558518.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
LDLR | ENST00000558518.6 | c.901G>T | p.Asp301Tyr | missense_variant | 6/18 | 1 | NM_000527.5 | P3 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome Cov.: 32
GnomAD4 exome
Cov.:
32
GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Hypercholesterolemia, familial, 1 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | literature only | LDLR-LOVD, British Heart Foundation | Mar 25, 2016 | - - |
Familial hypercholesterolemia Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Sep 23, 2022 | For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Asp301 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9090532, 11600564, 15241806, 16250003, 25461735, 25463123). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. ClinVar contains an entry for this variant (Variation ID: 251512). This variant is also known as D280Y. This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 12417285, 31491741). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces aspartic acid, which is acidic and polar, with tyrosine, which is neutral and polar, at codon 301 of the LDLR protein (p.Asp301Tyr). - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Pathogenic
D;.;.;.;.;.
Eigen
Pathogenic
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Pathogenic
D;D;D;D;D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
H;.;.;.;.;H
MutationTaster
Benign
D;D;D;D;D;D;D
PrimateAI
Benign
T
PROVEAN
Pathogenic
D;D;D;D;D;D
Sift
Pathogenic
D;D;D;D;D;D
Sift4G
Pathogenic
D;D;D;D;D;D
Polyphen
D;.;.;.;.;.
Vest4
MutPred
Loss of disorder (P = 0.0146);Loss of disorder (P = 0.0146);.;.;.;Loss of disorder (P = 0.0146);
MVP
MPC
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at