19-11105258-G-T
Variant names:
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PM2PP3_ModeratePP5_Very_Strong
The NM_000527.5(LDLR):c.352G>T(p.Asp118Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.00000411 in 1,461,302 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 Likely pathogenic (★★).
Frequency
Genomes: not found (cov: 33)
Exomes 𝑓: 0.0000041 ( 0 hom. )
Consequence
LDLR
NM_000527.5 missense
NM_000527.5 missense
Scores
8
9
2
Clinical Significance
Conservation
PhyloP100: 4.37
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 14 ACMG points.
PM1
In a disulfide_bond (size 12) in uniprot entity LDLR_HUMAN there are 22 pathogenic changes around while only 1 benign (96%) in NM_000527.5
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.901
PP5
Variant 19-11105258-G-T is Pathogenic according to our data. Variant chr19-11105258-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 183085.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-11105258-G-T is described in Lovd as [Pathogenic]. Variant chr19-11105258-G-T is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
LDLR | NM_000527.5 | c.352G>T | p.Asp118Tyr | missense_variant | Exon 4 of 18 | ENST00000558518.6 | NP_000518.1 |
Ensembl
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 genomes
Cov.:
33
GnomAD3 exomes AF: 0.0000120 AC: 3AN: 250932Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135810
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GnomAD4 exome AF: 0.00000411 AC: 6AN: 1461302Hom.: 0 Cov.: 33 AF XY: 0.00000688 AC XY: 5AN XY: 726974
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GnomAD4 genome Cov.: 33
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:12Uncertain:1Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Hypercholesterolemia, familial, 1 Pathogenic:5Uncertain:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratory of molecular diagnosis of dyslipidemias, Università egli studi di Napoli Federico II | May 24, 2021 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital | Sep 03, 2015 | - - |
Likely pathogenic, criteria provided, single submitter | literature only | LDLR-LOVD, British Heart Foundation | Mar 25, 2016 | - - |
Uncertain significance, flagged submission | 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 | research | Brunham Lab, Centre for Heart and Lung Innovation, University of British Columbia | May 10, 2019 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Nov 13, 2023 | The c.352G>T (p.Asp118Tyr) variant of the LDLR gene, that encodes for low density lipoprotein receptor, has been identified in heterozygous status in several unrelated individuals (>10) who fulfill the clinical criteria of Familial Hypercholesterolemia (FH) (PMID:10978268, 11317362, 17196209, 20045108, 23375686, 28965616, 28958694). This variant has also been reported in homozygous or compound heterozygous status in multiple affected individuals (at least 6) with severe FH (PMID:10978268, 11317362, 23375686, 9974426, 28965616). In-vitro functional studies on cultured patient derived fibroblasts have shown that this variant results in 30% of normal LDLR activity when compound heterozygote with another well-known pathogenic variant, p.Val523Met (ClinVar ID: 3696) (PMID: 9974426, 23375686). This variant lies in the mutational hot spot (amino acids 105-232) of a well-established functional domain critical for LDLR protein function. This variant is found to be rare (3/250932; 0.00001196) in the general population database (gnomAD) and interpreted as likely pathogenic by several submitters in the ClinVar database (ClinVar ID: 183085). Therefore, the c.352G>T (p.Asp118Tyr) variant in LDLR gene is classified as likely pathogenic. - |
Familial hypercholesterolemia Pathogenic:3
Likely pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Dec 05, 2023 | This missense variant replaces aspartic acid with tyrosine at codon 118 of the LDLR protein. This variant is also known as p.Asp97Tyr in the mature protein, and FH Naples 3 in the literature. This variant alters a conserved AA1 residue in the LDLR type A repeat 3 of the LDLR protein (a.a. 107-145), 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. A functional study has shown that this variant results in 30% of normal LDLR activity when in compound heterozygous state with a different pathogenic LDLR missense variant (PMID: 9974426). This variant has shown an unclear functional consequence in a high throughput screening assay in HeLa cells (PMID: 25647241). This LDLR variant has been reported in over 10 heterozygous individuals affected with familial hypercholesterolemia (PMID: 9974426, 28161202, 28965616, 28958694, 31947532, 35795214; Color internal data). This variant has also been observed in compound heterozygous state with a known pathogenic LDLR variant in at least two individuals affected with severe homozygous familial hypercholesterolemia, a phenotype expected of having two deleterious LDLR variants (PMID: 23375686, 31947532, 36325061). This variant has been identified in 3/250932 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 20, 2024 | This sequence change replaces aspartic acid, which is acidic and polar, with tyrosine, which is neutral and polar, at codon 118 of the LDLR protein (p.Asp118Tyr). This variant is present in population databases (rs730882080, gnomAD 0.003%). This missense change has been observed in individuals with LDLR-related conditions (PMID: 9974426, 11317362, 23375686, 25487149, 28161202, 28965616, 31345425). Invitae Evidence Modeling of clinical and family history, age, sex, and reported ancestry of multiple individuals with this LDLR variant has been performed. This variant is expected to be pathogenic with a positive predictive value of at least 99%. This is a validated machine learning model that incorporates the clinical features of 363,995 individuals referred to our laboratory for LDLR testing. This variant is also known as D97Y, FH-Napoli-3 or Naples-3. ClinVar contains an entry for this variant (Variation ID: 183085). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt LDLR protein function with a positive predictive value of 95%. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on LDLR function (PMID: 25647241). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Apr 01, 2024 | Variant summary: LDLR c.352G>T (p.Asp118Tyr) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 250932 control chromosomes. c.352G>T has been reported in the literature in multiple heterozygous individuals affected with Familial Hypercholesterolemia, as well as multiple compound heterozygous individuals affected with Homozygous Familial Hypercholesterolemia (e.g., Bertolini_1999, Scicali_2018, Di Taranto_2020, Du_2022). These data indicate that the variant is very likely to be associated with disease. Two publications report experimental evidence evaluating an impact on protein function, however, none of these studies allow convincing conclusions about the variant effect. One study demonstrates that LDLR activity in an individual with the variant is approximately 30%, however this individual also carried the pathogenic variant p.V523M (Betolini_1999). Another study investigating whether this variant is disruptive demonstrated unclear results (Thormaehlen_2015). The following publications have been ascertained in the context of this evaluation (PMID: 9974426, 31947532, 36325061, 28958694, 25647241). ClinVar contains an entry for this variant (Variation ID: 183085). Based on the evidence outlined above, the variant was classified as pathogenic. - |
not provided Pathogenic:2Other:1
not provided, no classification provided | in vitro | Dept. of Genetics and Pharmacogenomics, Merck Research Labs | - | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | AiLife Diagnostics, AiLife Diagnostics | Jan 19, 2022 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Aug 12, 2024 | Identified in the heterozygous and compound heterozygous state with a second LDLR variant in patients with hypercholesterolemia in published literature (PMID: 9974426, 28965616, 34297352, 35339733, 32977124); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as p.(D97Y); This variant is associated with the following publications: (PMID: 9974426, 23375686, 25647241, 35339733, 25487149, 28965616, 34297352, 32977124, 30583242, 34906454) - |
Homozygous familial hypercholesterolemia Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jul 15, 2020 | The p.Asp118Tyr variant in LDLR has been identified in the heterozygous state in at least 6 individuals with hypercholesterolemia and segregated with disease in > 4 affected relatives with definite or probable familial hypercholesterolemia (FH) from at least 2 families (Bertolini 1999 PMID: 9974426, Bertolini 2000 PMID: 10978268, Liguori 2001 PMID: 11317362, Campagna 2008 PMID: 17196209, Romano 2010 PMID: 20045108, Bertolini 2013 PMID: 23375686, Scicali 2017 PMID: 28958694, Pirillo 2017 PMID: 28965616, Trinder 2019 PMID: 31345425). It has also been reported in 1 homozygote and 3 compound heterozygotes (with additional pathogenic LDLR variants) with hypercholesterolemia, at least 3 of whom had a more severe presentation (Bertolini 2000 PMID: 10978268, Liguori 2001 PMID: 11317362, Campagna 2008 PMID: 17196209, Bertolini 2013 PMID: 23375686). Additionally, this variant has been reported in 2 individuals with early myocardial infarction (Thormaehlen 2015 PMID: 25647241). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID: 183085) and has also been identified in 0.003% (3/111436) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). In vitro functional studies suggest that the variant has only a mild impact protein function (Bertolini 2013 PMID: 23375686, Thormaehlen 2015 PMID: 25647241). Computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant FH. ACMG/AMP Criteria applied: PS4_Moderate, PM3, PP1, PM2_Supporting. - |
Cardiovascular phenotype Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 06, 2023 | The p.D118Y variant (also known as c.352G>T), located in coding exon 4 of the LDLR gene, results from a G to T substitution at nucleotide position 352. The aspartic acid at codon 118 is replaced by tyrosine, an amino acid with highly dissimilar properties. This alteration, also known as p.D97Y, has been reported primarily in Italian familial hypercholesterolemia (FH) cohorts (Bertolini S et al. Arterioscler. Thromb. Vasc. Biol., 1999 Feb;19:408-18; Liguori R et al. Hum. Mutat., 2001 May;17:433; Campagna F et al. Atherosclerosis, 2008 Jan;196:356-64; Romano M et al. Atherosclerosis, 2010 Jun;210:493-6; Minicocci I et al. J. Pediatr., 2017 Apr;183:100-107.e3; Scicali R et al. Nutr Metab Cardiovasc Dis, 2018 Jan;28:35-43). Reduced LDL-R activity (30% of the control) was reported in a compound heterozygous FH patient who also carried the p.V523M pathogenic mutation (Bertolini S et al. Arterioscler. Thromb. Vasc. Biol., 1999 Feb;19:408-18). Based on internal structural analysis, this variant is predicted to disrupt a linear motif (Ambry internal data). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. - |
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
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D;D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D
MetaSVM
Uncertain
D
MutationAssessor
Uncertain
M;.;.;M
PrimateAI
Benign
T
PROVEAN
Uncertain
D;D;D;D
REVEL
Pathogenic
Sift
Uncertain
D;D;D;D
Sift4G
Uncertain
D;D;D;D
Polyphen
D;.;.;.
Vest4
MutPred
Loss of loop (P = 0.1258);Loss of loop (P = 0.1258);.;Loss of loop (P = 0.1258);
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