rs763998635
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1PM2PP5_Very_Strong
The NM_000527.5(LDLR):c.473C>G(p.Ser158Cys) 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 (★★). Synonymous variant affecting the same amino acid position (i.e. S158S) has been classified as Likely benign.
Frequency
Genomes: not found (cov: 33)
Consequence
LDLR
NM_000527.5 missense
NM_000527.5 missense
Scores
3
9
6
Clinical Significance
Conservation
PhyloP100: 0.911
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 12 ACMG points.
PM1
?
In a hotspot region, there are 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 8 uncertain in NM_000527.5
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 19-11105379-C-G is Pathogenic according to our data. Variant chr19-11105379-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 251245.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-11105379-C-G is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
LDLR | NM_000527.5 | c.473C>G | p.Ser158Cys | missense_variant | 4/18 | ENST00000558518.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
LDLR | ENST00000558518.6 | c.473C>G | p.Ser158Cys | missense_variant | 4/18 | 1 | NM_000527.5 | P3 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 genomes
?
Cov.:
33
GnomAD4 exome Cov.: 33
GnomAD4 exome
Cov.:
33
GnomAD4 genome ? Cov.: 33
GnomAD4 genome
?
Cov.:
33
ClinVar
Significance: Likely pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Hypercholesterolemia, familial, 1 Pathogenic:2
Likely pathogenic, criteria provided, single submitter | research | Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge | Mar 01, 2016 | 0/190 non-FH alleles - |
Likely pathogenic, criteria provided, single submitter | literature only | LDLR-LOVD, British Heart Foundation | Mar 25, 2016 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Benign
CADD
Benign
DANN
Uncertain
DEOGEN2
Pathogenic
D;.;.;.
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
D
LIST_S2
Uncertain
D;D;D;D
M_CAP
Pathogenic
D
MetaRNN
Uncertain
D;D;D;D
MetaSVM
Uncertain
D
MutationAssessor
Uncertain
M;.;.;M
MutationTaster
Benign
N;N;N;N;N;N;N
PrimateAI
Benign
T
PROVEAN
Uncertain
D;D;D;D
Sift
Uncertain
D;D;D;D
Sift4G
Uncertain
D;D;D;D
Polyphen
D;.;.;.
Vest4
MutPred
Loss of glycosylation at S158 (P = 0.02);Loss of glycosylation at S158 (P = 0.02);.;Loss of glycosylation at S158 (P = 0.02);
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