19-11105369-T-G
Position:
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_000527.5(LDLR):c.463T>G(p.Cys155Gly) 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C155F) has been classified as Likely pathogenic.
Frequency
Genomes: not found (cov: 33)
Consequence
LDLR
NM_000527.5 missense
NM_000527.5 missense
Scores
13
4
2
Clinical Significance
Conservation
PhyloP100: 7.91
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 domain LDL-receptor class A 4 (size 40) in uniprot entity LDLR_HUMAN there are 71 pathogenic changes around while only 3 benign (96%) 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 chr19-11105370-G-T is described in Lovd as [Likely_pathogenic].
PP3
MetaRNN computational evidence supports a deleterious effect, 0.995
PP5
Variant 19-11105369-T-G is Pathogenic according to our data. Variant chr19-11105369-T-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 251239.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-11105369-T-G is described in Lovd as [Pathogenic]. Variant chr19-11105369-T-G is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| LDLR | NM_000527.5 | c.463T>G | p.Cys155Gly | missense_variant | 4/18 | ENST00000558518.6 | NP_000518.1 |
Ensembl
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
33
GnomAD4 exome Cov.: 33
GnomAD4 exome
Cov.:
33
GnomAD4 genome
GnomAD4 genome
Cov.:
33
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:12
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Hypercholesterolemia, familial, 1 Pathogenic:7
| Pathogenic, criteria provided, single submitter | clinical testing | MGZ Medical Genetics Center | Jul 01, 2022 | - - |
| Likely pathogenic, criteria provided, single submitter | literature only | LDLR-LOVD, British Heart Foundation | Mar 25, 2016 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille | Mar 30, 2017 | - - |
| Pathogenic, no assertion criteria provided | research | Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum | - | - - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix | Dec 16, 2016 | - - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Robarts Research Institute, Western University | Jan 02, 2018 | - - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Genetics and Molecular Pathology, SA Pathology | Dec 16, 2022 | The LDLR c.463T>G variant is classified as LIKELY PATHOGENIC (PS4_Moderate, PM1, PM2, PP3, PP4) The LDLR c.463T>G variant is a single nucleotide change in exon 4 of 18 of the LDLR gene, which is predicted to change the amino acid cysteine at position 155 in the protein to glycine. This variant has been reported in a number of individuals affected with familial hypercholesterolemia (PMID: 33955087, 10735632, 14974088, 9104431, 33740630) (PS4_Mod). Note this variant has also been described as Cys134Gly or FH Germany in the literature. The cysteine residue is highly conserved across species and is located in a region that is involved in disulphide bond formation, which is critical for protein structure, stability and binding (PMID: 7603991) (PM1). This variant is absent from population databases (PM2) and has been reported as Pathogenic/Likely pathogenic by other diagnostic laboratories (ClinVar Variation ID: 251239). This variant is also reported in dbSNP (rs879254535), LOVD (LDLR_001739) and HGMD (CM920414). Computational predictions support a deleterious effect on the gene or gene product (PP3). The clinical features of this case are highly specific for a variant in the LDLR gene and this patient has a well-defined syndrome with little overlap with other clinical presentations (PP4). - |
not provided Pathogenic:3
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jan 25, 2022 | Not observed in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Participates in disulfide bonding with another cysteine residue which is critical for correct protein structure, and is located in the LDL-receptor class A4 repeat domain which is necessary for ligand binding (Sudhof et al., 1985; Rudenko et al., 2002); Different missense changes at this residue, p.(C155R), p.(C155F), p.(C155Y), have been reported in the Human Gene Mutation Database in association with FH (HGMD); Also known as p.(C134G) and FH Germany; Reported in ClinVar but additional evidence is not available (ClinVar Variant ID#251239; ClinVar); This variant is associated with the following publications: (PMID: 32041611, 33740630, 1301956, 10735632, 10090473, 9104431, 14974088, 26894473) - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics | Nov 22, 2017 | - - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Dec 01, 2021 | - - |
Cardiovascular phenotype Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 19, 2022 | The p.C155G pathogenic mutation (also known as c.463T>G), located in coding exon 4 of the LDLR gene, results from a T to G substitution at nucleotide position 463. The cysteine at codon 155, located at LDLR class A repeat 4, is replaced by glycine, an amino acid with highly dissimilar properties. Pathogenic LDLR mutations that result in the substitution or generation of cysteine residues within the cysteine-rich LDLR class A repeats and EGF-like domains are common in familial hypercholesterolemia (FH) (Villéger L. Hum Mutat. 2002;20(2):81-7). This variant (also known as p.C134G and FH Germany) has been reported in multiple FH cohorts in heterozygous and compound heterozygote cases (Hobbs HH et al. Hum. Mutat. 1992;1:445-66; Lombardi MP et al. Clin. Genet. 2000 Feb;57:116-24; Dedoussis GV et al. Hum. Mutat. 2004 Mar;23:285-6; Koeijvoets KC et al. Atherosclerosis. 2005 May;180:93-9; Sanna C et al. Atherosclerosis. 2016 Apr;247:97-104). Alternate amino acid substitutions at this position, including p.C155R and p.C155F, have also been reported in individuals with FH (Yu W et al. Atherosclerosis. 2002 Dec;165:335-42; van der Graaf A et al. Circulation. 2011 Mar;123:1167-73). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. - |
Familial hypercholesterolemia Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 07, 2022 | 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. For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Cys155 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been observed in individuals with LDLR-related conditions (PMID: 9104431, 10735632, 14974088, 20809525, 21382890), which suggests that this may be a clinically significant amino acid residue. This variant affects a cysteine residue located within an LDLRA or epidermal-growth-factor (EGF)-like domains of the LDLR protein. Cysteine residues in these domains have been shown to be involved in the formation of disulfide bridges, which are critical for protein structure and stability (PMID: 7548065, 7603991, 7979249). In addition, missense substitutions within the LDLRA and EGF-like domains affecting cysteine residues are overrepresented among patients with hypercholesterolemia (PMID: 18325082). ClinVar contains an entry for this variant (Variation ID: 251239). This variant is also known as C134G and FH Germany. This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 9104431, 10735632, 14974088). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces cysteine, which is neutral and slightly polar, with glycine, which is neutral and non-polar, at codon 155 of the LDLR protein (p.Cys155Gly). - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Benign
DEOGEN2
Pathogenic
D;.;.;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D;D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
H;.;.;H
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;D;D;D
REVEL
Pathogenic
Sift
Uncertain
D;D;D;D
Sift4G
Uncertain
D;D;D;D
Polyphen
D;.;.;.
Vest4
MutPred
Loss of stability (P = 0.002);Loss of stability (P = 0.002);.;Loss of stability (P = 0.002);
MVP
MPC
ClinPred
D
GERP RS
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