rs121908024
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000527.5(LDLR):c.97C>T(p.Gln33Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,424 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 Pathogenic (★★★).
Frequency
Genomes: not found (cov: 33)
Exomes 𝑓: 0.0000027 ( 1 hom. )
Consequence
LDLR
NM_000527.5 stop_gained
NM_000527.5 stop_gained
Scores
3
3
1
Clinical Significance
Conservation
PhyloP100: 2.55
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.
PVS1
?
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 2407 pathogenic variants in the truncated region.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 19-11100252-C-T is Pathogenic according to our data. Variant chr19-11100252-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 3683.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr19-11100252-C-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
LDLR | NM_000527.5 | c.97C>T | p.Gln33Ter | stop_gained | 2/18 | ENST00000558518.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
LDLR | ENST00000558518.6 | c.97C>T | p.Gln33Ter | stop_gained | 2/18 | 1 | NM_000527.5 | P3 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 genomes
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Cov.:
33
GnomAD3 exomes AF: 0.00000796 AC: 2AN: 251156Hom.: 1 AF XY: 0.00 AC XY: 0AN XY: 135732
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GnomAD4 exome AF: 0.00000274 AC: 4AN: 1461424Hom.: 1 Cov.: 31 AF XY: 0.00000275 AC XY: 2AN XY: 726996
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GnomAD4 genome ? Cov.: 33
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:18
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
Hypercholesterolemia, familial, 1 Pathogenic:12
Pathogenic, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | May 31, 2023 | The c.97C>T (p.Gln33*) variant in the LDLR gene is located on the exon 2 and introduces a premature translation termination codon (p.Gln33*), resulting in an absent or disrupted protein product. The variant has been identified in more than 10 unrelated individuals with familial hypercholesterolemia (FH) (PMID: 33418990, 28475941, 28235710, 32759540, 18096825). This variant segregates with FH phenotype in at least 3 informative meioses in 1 family and 1 informative meiosis in 7 families from different laboratories according to the ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel. Experimental study of LDLR expression with heterozygous and homozygous patient fibroblasts confirmed the negative functional impact of the variant (PMID: 2088165, 31358055, 28645073). The variant is reported in ClinVar (ID: 3683) and evaluated as pathogenic by the Expert Panel. Loss-of-function variants in LDLR are known to be pathogenic (PMID: 20809525, 21310417). This variant is rare in the general population according to gnomAD (2/251156). Therefore, the c.97C>T (p.Gln33*) variant of LDLR has been classified as pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Department of Human Genetics, Laborarztpraxis Dres. Walther, Weindel und Kollegen | Dec 07, 2018 | At protein level, the mutation leads to a premature termination of protein biosynthesis after 33 amino acids (12th amino acid of the mature protein). This change has already been described in the literature as FH Turkey and FH Milan-4, as well as in patients with familial hypercholesterolemia and is associated with elevated cholesterol and LDL-C levels. Most likely the mutation leads to a complete loss of LDL receptor activity due to premature degradation. PMID: 1301940, 15701167 - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Nov 01, 1988 | - - |
Pathogenic, criteria provided, single submitter | research | Laboratory of Genetics and Molecular Cardiology, University of São Paulo | Mar 01, 2016 | - - |
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 | subjects mutated among 2600 FH index cases screened = 12 , family members = 6 with co-segregation - |
Pathogenic, criteria provided, single submitter | research | Fundacion Hipercolesterolemia Familiar | Mar 01, 2016 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille | Mar 30, 2017 | ACMG Guidelines: Pathogenic (ii) - |
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jul 02, 2021 | - - |
Pathogenic, no assertion criteria provided | research | Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory of molecular diagnosis of dyslipidemias, Università egli studi di Napoli Federico II | May 24, 2021 | - - |
Pathogenic, criteria provided, single submitter | literature only | LDLR-LOVD, British Heart Foundation | Mar 25, 2016 | - - |
Pathogenic, reviewed by expert panel | curation | ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel | Apr 30, 2022 | NM_000527.5(LDLR):c.97C>T (p.Gln33Ter) variant is classified as pathogenic for Familial Hypercholesterolemia by applying evidence code PVS1, PS3, PS4, PM2, PP1 and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: PM2 - PopMax MAF = 0.00001759 (0.002%) in European non-Finnish exomes (gnomAD v2.1.1). PVS1 - Variant leads to stop at codon 33, amino-terminal of amino acid 830. PS3 - Two studies contribute to PS3 attribution. One (PMID:2088165) report a level 2 assay performed on homozygous patient's fibroblasts with radiolabeled LDL consistent with damaging effect of the variant (< 2% LDLR activity). The second reports a level 1 assay perfomed on Heterologous cells (CHO-ldlA7). FACS, CLSM and WB results in 10% expression, binding and uptake of LDLR which is retained in the ER. PS4 - Variant meets PM2 and is identified in at least 10 unrelated index cases from CGMC UFGOD (APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière). 8 cases fulfil SB possible criteria and 14 fulfil DLCN >= 6 criteria. PP1_Strong- Variant segregate with FH in at least 3 informatives meiosis (LDL-C > 75th percentile) from 1 family from CGMC, UFGOD (APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière). In the same Laboratory segregation with FH was observed in 1 informative meiosis from 7 families. PP4 - Variant meets PM2 and is identified in 22 unrelated index cases from CGMC UFGOD (APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière). - |
Familial hypercholesterolemia Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jul 24, 2023 | This variant changes 1 nucleotide in exon 2 in the LDLR type A repeat 1 of the LDLR gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. An experimental functional study using transfected CHO-ldlA7 cells has shown that this variant causes a significant reduction in LDLR activity, LDL uptake, and LDL binding (PMID: 28645073). This LDLR variant has been reported in over 10 heterozygous individuals affected with familial hypercholesterolemia (PMID: 15241806, 15791167, 16250003, 18096825, 23375686, 34037665). This variant has also been observed in homozygous state in several individuals affected with severe homozygous familial hypercholesterolemia (PMID: 2088165, 1301940, 1301956, 9974426, 24088637, 27784735). This variant has been identified in 2/251156 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of LDLR function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 10, 2023 | This sequence change creates a premature translational stop signal (p.Gln33*) in the LDLR gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in LDLR are known to be pathogenic (PMID: 20809525, 28645073). This variant is present in population databases (rs121908024, gnomAD 0.002%), including at least one homozygous and/or hemizygous individual. This premature translational stop signal has been observed in individual(s) with familial hypercholesterolemia (PMID: 1301940, 15241806, 15701167, 18096825, 24088637, 27784735). This variant is also known as p.Gln12X. ClinVar contains an entry for this variant (Variation ID: 3683). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Mar 18, 2021 | - - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Nov 18, 2021 | Also known as p.(Q12*), FH Turkey and FH Milan-4; Not observed at significant frequency in large population cohorts (Lek et al., 2016); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Published functional studies show that this variant results in loss of protein function (Jiang et al., 2017); Reported in ClinVar as a pathogenic variant (ClinVar Variant ID# 3683; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 9974426, 15701167, 24088637, 25487149, 15241806, 1301940, 1301956, 32977124, 33740630, 34037665, 31358055, 28645073, 2088165) - |
Pathogenic, no assertion criteria provided | provider interpretation | Stanford Center for Inherited Cardiovascular Disease, Stanford University | Jun 09, 2017 | p.Gln33* (also known as p.Gln12X in the literature) (c.97C>T) in the LDLR gene (NM_000527.4) Given that this variant truncates the LDL receptor, the very strong case data and the variant's rarity in large population databases, we consider this variant pathogenic and we do feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). The variant has been seen in at least 25 unrelated cases of FH (not including this patient's family). There is strong cases data. This variant is listed in ClinVar and is classified as pathogenic by Invitae, LDL-LOVD British Heart Foundation (seen in 5 patients) and the Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies,APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix (seen in 12 patients from 6 families out of 2600 index cases). Loux et al (1992, PMID1301940) found this variant (reported as p.Gln12*) in one of seven families with FH. The proband had homozygous FH, with total cholesterol levels in the 600s. Mozas et al (2004, PMID 15241806) found this variant in 2 out of 476 Spanish patients with FH. Zakharova et al (2005, PMID 15701167) found this variant in 2 out of 45 Russian patients (from the same family) with a clinical diagnosis of FH. Junyent et al (2008, PMID 18096825) found this variant in 2 of 146 Spanish patients. It is unclear whether or not these patients are related. Meng et al (2013, PMID 24088637) present a case report of a 12-year-old male with apparently Compound homozygous FH, and his father with heterozygous FH and the same variant. Sánchez-Hernández et al (2016, PMID 27784735) found this variant in 4 out of 97 patients: this variant was present in 2 patients in the homozygous form and 2 patient in the compound heterozygous form. Thirteen other variants at this and nearby codons (p.Glu28Ter, p.Arg29Ter, p.Glu31Ter, p.Glu31Lys, p.Glu31Aspfs, p.Phe32Cys, p.Gln33Hisfs, p.Cys34Gly, p.Cys34Ser, p.Cys34Ter, p.Gln35Ter, p.Asp36Glufs, p.Asp36Glu) are considered pathogenic in ClinVar. This variant is completely conserved across species and nearby residues are also strongly conserved. The variant is reported online in the Genome Aggregation Consortium Dataset (gnomAD; http://gnomad.broadinstitute.org/), which currently includes variant calls on >140,000 unrelated individuals of African, Asian, European, Ashkenazi, Latino descent. It is present in 1 European individual in the homozygous form out of 122,871 individuals in this database. The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease. This variant was absent from 288 controls (Loux et al 1992; Junyent et al 2008) - |
Cardiovascular phenotype Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 21, 2022 | The p.Q33* pathogenic mutation (also known as c.97C>T), located in coding exon 2 of the LDLR gene, results from a C to T substitution at nucleotide position 97. This changes the amino acid from a glutamine to a stop codon within coding exon 2. This alteration has been reported in association with familial hypercholesterolemia across various ethnicities (also reported as p.Q12X) (Hobbs HH, Annu. Rev. Genet. 1990 ; 24:133-70; Mozas P, Hum. Mutat. 2004 Aug; 24(2):187; Zakharova FM, BMC Med. Genet. 2005 Feb;6:6; Fouchier SW, Hum. Mutat. 2005 Dec; 26(6):550-6). This alteration was also reported in a homozygous state in two individuals who both had total cholesterol levels greater than 600 mg/dl (Loux N, Hum. Mutat. 1992;1(4):325-32; Meng X, Indian J Ophthalmol 2013 Dec; 61(12):770-1). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Uncertain
Eigen
Pathogenic
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
MutationTaster
Benign
A;A;A;A;A;A;D
Vest4
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
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