rs730882098
Positions:
Variant summary
Our verdict is Likely pathogenic. Variant got 10 ACMG points: 10P and 0B. PS4_ModeratePP1_ModeratePM2PP3PP4PM3
This summary comes from the ClinGen Evidence Repository: NM_000527.5(LDLR):c.1133A>C (p.Gln378Pro) variant is classified as likely pathogenic for Familial Hypercholesterolemia by applying evidence code PM2, PS4_Moderate, PM3, PP1_Moderate, PP3, 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 = 0.00001760 (0.001760%) in European (non-Finnish) exomes (gnomAD v2.1.1).PP3: REVEL = 0.754.PP1_moderate: Variant segregates with FH phenotype in at least 4 informative meiosis from 1 family from Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation).PS4_moderate: Variant meets PM2 and is identified in at least 6 unrelated index cases: 1 case from Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation) with Simon Broome definite criteria; 1 case from Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA) with Dutch lipid clinic network >=6; 1 case from Mayo Clinic Atherosclerosis and Lipid Genomics Laboratory with Dutch lipid clinic network >=6; 1 case from South Africa in PMID:9664576; 1 case from Spain in PMID:15241806; 1 case from Italy in PMID:23375686.PM3: PMID:27784735 - variant identified in two children with homozygous FH: in one patient confirmed in trans with LDLR p.Ile792Thr and in the second patient confirmed in trans with a LP/P LDLR exonic deletion; given this exonic deletion is LP/P, PM3 applies.PP4: Variant meets PM2 and is identified in >1 index case who fulfill clinical criteria for FH, after alternative causes of high cholesterol were excluded.Note: BS3 not met: PMID:32015373 - Level 1 assay: Heterologous cells, FACS assays – results - cell surface LDLR (96%), binding (101%) were normal; LDL uptake (80%) activity is not above 90%, so BS3 not met. This result suggests this variant may only have a minor effect (i.e. 20% reduction in LDL uptake), although this is not insignificant. LINK:https://erepo.genome.network/evrepo/ui/classification/CA023422/MONDO:0007750/013
Frequency
Genomes: not found (cov: 31)
Exomes đť‘“: 0.000012 ( 0 hom. )
Consequence
LDLR
NM_000527.5 missense
NM_000527.5 missense
Scores
8
7
4
Clinical Significance
Conservation
PhyloP100: 9.11
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 Likely_pathogenic. Variant got 10 ACMG points.
PS4
For more information check the summary or visit ClinGen Evidence Repository.
PM2
For more information check the summary or visit ClinGen Evidence Repository.
PM3
For more information check the summary or visit ClinGen Evidence Repository.
PP1
For more information check the summary or visit ClinGen Evidence Repository.
PP3
For more information check the summary or visit ClinGen Evidence Repository.
PP4
For more information check the summary or visit ClinGen Evidence Repository.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| LDLR | NM_000527.5 | c.1133A>C | p.Gln378Pro | missense_variant | 8/18 | ENST00000558518.6 | NP_000518.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| LDLR | ENST00000558518.6 | c.1133A>C | p.Gln378Pro | missense_variant | 8/18 | 1 | NM_000527.5 | ENSP00000454071.1 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
31
GnomAD3 exomes AF: 0.00000796 AC: 2AN: 251308Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135874
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GnomAD4 exome AF: 0.0000123 AC: 18AN: 1461580Hom.: 0 Cov.: 32 AF XY: 0.0000124 AC XY: 9AN XY: 727108
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ClinVar
Significance: Likely pathogenic
Submissions summary: Pathogenic:11Uncertain:4Other:1
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
Hypercholesterolemia, familial, 1 Pathogenic:5Uncertain:3
| Uncertain significance, criteria provided, single submitter | research | Fundacion Hipercolesterolemia Familiar | Mar 01, 2016 | - - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Robarts Research Institute, Western University | - | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation | Nov 05, 2016 | - - |
| Uncertain significance, criteria provided, single submitter | literature only | LDLR-LOVD, British Heart Foundation | Mar 25, 2016 | - - |
| Likely pathogenic, reviewed by expert panel | curation | ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel | May 06, 2022 | NM_000527.5(LDLR):c.1133A>C (p.Gln378Pro) variant is classified as likely pathogenic for Familial Hypercholesterolemia by applying evidence code PM2, PS4_Moderate, PM3, PP1_Moderate, PP3, 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 = 0.00001760 (0.001760%) in European (non-Finnish) exomes (gnomAD v2.1.1). PP3: REVEL = 0.754. PP1_moderate: Variant segregates with FH phenotype in at least 4 informative meiosis from 1 family from Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation). PS4_moderate: Variant meets PM2 and is identified in at least 6 unrelated index cases: 1 case from Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation) with Simon Broome definite criteria; 1 case from Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA) with Dutch lipid clinic network >=6; 1 case from Mayo Clinic Atherosclerosis and Lipid Genomics Laboratory with Dutch lipid clinic network >=6; 1 case from South Africa in PMID: 9664576; 1 case from Spain in PMID: 15241806; 1 case from Italy in PMID: 23375686. PM3: PMID: 27784735 - variant identified in two children with homozygous FH: in one patient confirmed in trans with LDLR p.Ile792Thr and in the second patient confirmed in trans with a LP/P LDLR exonic deletion; given this exonic deletion is LP/P, PM3 applies. PP4: Variant meets PM2 and is identified in >1 index case who fulfill clinical criteria for FH, after alternative causes of high cholesterol were excluded. Note: BS3 not met: PMID: 32015373 - Level 1 assay: Heterologous cells, FACS assays – results - cell surface LDLR (96%), binding (101%) were normal; LDL uptake (80%) activity is not above 90%, so BS3 not met. This result suggests this variant may only have a minor effect (i.e. 20% reduction in LDL uptake), although this is not insignificant. - |
| Likely pathogenic, criteria provided, single submitter | research | Brunham Lab, Centre for Heart and Lung Innovation, University of British Columbia | Mar 13, 2019 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille | Mar 30, 2017 | - - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Sep 18, 2024 | The c.1133A>C (p.Gln378Pro) variant, also known as p.Gln357Pro in LDLR gene, that encodes for low density lipoprotein receptor, has been identified in multiple individuals (>10) affected with familial hypercholesterolemia (FH), and segregate with the FH phenotype in at least four informative meiosis from one family (PMID:9664576, 15241806, 15556093, 19007590, 19118540, 19446849, 20145306, 21310417, 23375686, ClinGen review [ClinVar ID: 183108]). This variant has also been reported in compound heterozygous status with a loss-of-function variant in an individual with severe FH (PMID: 27784735, ClinGen review [ClinVar ID: 183108]). Computational prediction tools suggest that the p.Gln378Pro variant may have deleterious effect on the protein function (REVEL score: 0.754). This variant is rare (18/1613916 chromosomes; 0.001115%) in the general population database, gnomAD (v4.1.0) and interpreted as likely pathogenic/pathogenic by multiple submitters in the ClinVar database including the ClinGen familial hypercholesterolemia variant curation expert panel (ClinVar ID: 183108). Therefore, the c.1133A>C (p.Gln378Pro) variant in LDLR gene is classified as likely pathogenic. - |
Familial hypercholesterolemia Pathogenic:3Uncertain:1
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 20, 2024 | This sequence change replaces glutamine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 378 of the LDLR protein (p.Gln378Pro). This variant is present in population databases (rs730882098, gnomAD 0.0009%). This missense change has been observed in individual(s) with hypercholesterolemia (PMID: 9664576, 15241806, 19007590, 19446849, 20145306, 22698793, 23375686). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as p.Gln357Pro. ClinVar contains an entry for this variant (Variation ID: 183108). 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 with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jan 15, 2020 | This missense variant (also known as p.Gln357Pro in the mature protein) replaces glutamine with proline at codon 378 located in the EGF-like repeat B of the EGF precursor homology domain of the LDLR protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. In a high-throughput cell-based assay, this variant has shown unclear impact on LDLR function (PMID: 25647241). This variant has been reported in multiple individuals affected with familial hypercholesterolemia (PMID: 9664576, 15241806, 19446849, 20145306, 21310417, 22698793, 27784735, 23375686) and in two individuals affected with mixed hyperlipidemia (PMID: 19007590). This variant has been identified in 2/251308 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | National Institute of Allergy and Infectious Diseases - Centralized Sequencing Program, National Institutes of Health | Aug 06, 2021 | - - |
| Likely pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
not provided Pathogenic:1Other:1
| not provided, no classification provided | in vitro | Dept. of Genetics and Pharmacogenomics, Merck Research Labs | - | - - |
| Likely pathogenic, no assertion criteria provided | provider interpretation | Stanford Center for Inherited Cardiovascular Disease, Stanford University | Jan 09, 2018 | This variant was identified in a patient with familial hypercholesterolemia. Testing was performed at Invitae. Given the case data and rarity in general population databases we consider this variant likely pathogenic and we do feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). Alternate nomenclature for this variant: This variant is also known as p.Gln357Pro. The variant has been seen in at least 8 heterozygotes and 2 compound heterozygotes patients with FH. There is moderate case data and no segregation data. Callis et al. (1998) identified this variant in one patient with FH who was from the UK. Mozas et al. (2004) identified this variant in one patient with FH who was from Spain. Civeira et al. (2008) identified this variant in two female patients with clinical diagnosis of familial combined hyperlipidemia who were recruited from Spain. Senior author is the same as the Mozas paper so cases may be redundant. Guardamanga et al. (2009) reported this variant in a cohort of children recruited from Italy. The authors do not indicate how many patients had this variant. Chmara et al (2010) identified this variant in one patient with FH recruited from Poland. Tichy et al (2012) identified this variant in 1 patient with FH that was Czech. Bertolini et al (2013) identified this variant in 2 Italian patients with FH recruited from Genova, Modena, and and Palermo. The first author on this paper is the same as the last author on the Guardamanga paper and cases may overlap. Sanchez-Hernandez et al (2016) identified this variant two a children with homozygous FH. In one patient, the variant was seen in trans with LDLR p.Ile792Thr and in the other variant it was seen in trans with an unspecified deletion of LDLR. Per the lab report: "Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change." The variant is reported in 1 of 123,076 individuals listed 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, Latino, and Ashkenazi descent. Specifically, the variant was reported in 1 of 55821 European (NF) individuals (MAF = 0.0008957%). The average coverage at that site in gnomAD is 85x. - |
LDLR-related disorder Pathogenic:1
| Likely pathogenic, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | May 31, 2024 | The LDLR c.1133A>C variant is predicted to result in the amino acid substitution p.Gln378Pro. This variant has been previously reported in individuals with familial hypercholesterolemia (reported as Q357P in Callis et al. 1998. PubMed ID: 9664576; Tables S.3A and S.3B - Bertolini et al. 2013. PubMed ID: 23375686; Mozas et al. 2004. PubMed ID:15241806; Guardamagna et al. 2009. PubMed ID: 19446849; Chmara et al. 2010. PubMed ID: 20145306; TichĂ˝ et al. 2012. PubMed ID: 22698793). This variant is reported in 0.0018% of alleles in individuals of European (non-Finnish) descent in gnomAD, and it is interpreted as likely pathogenic by ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/183108/). This variant is interpreted as likely pathogenic. - |
Cardiovascular phenotype Pathogenic:1
| Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 19, 2024 | The p.Q378P variant (also known as c.1133A>C), located in coding exon 8 of the LDLR gene, results from an A to C substitution at nucleotide position 1133. The glutamine at codon 378 is replaced by proline, an amino acid with similar properties. This variant was reported in multiple individuals with features consistent with familial hypercholesterolemia (FH) (Callis M et al. Mol Cell Probes, 1998 Jun;12:149-52; Mozas P et al. Hum Mutat, 2004 Aug;24:187; Civeira F et al. J Am Coll Cardiol, 2008 Nov;52:1546-53; Guardamagna O et al. J Pediatr. 2009 Aug;155(2):199-204.e2; Chmara M et al. J Appl Genet, 2010;51:95-106; external communication; Ambry internal data). This variant has also been identified in conjunction with other LDLR variants in individuals with features consistent with homozygous FH; in at least one instance, the variants were identified in trans (Sánchez-Hernández RM et al. Circ Cardiovasc Genet, 2016 Dec;9:504-510). This amino acid position is poorly 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
Uncertain
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
Benign
T;T;T;T;T;T
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Benign
L;.;.;.;.;L
PrimateAI
Benign
T
PROVEAN
Uncertain
D;D;D;D;D;D
REVEL
Pathogenic
Sift
Uncertain
D;D;D;D;D;D
Sift4G
Uncertain
D;D;D;D;D;D
Polyphen
B;.;.;.;.;.
Vest4
MutPred
Gain of catalytic residue at Q378 (P = 0.0223);Gain of catalytic residue at Q378 (P = 0.0223);.;.;.;Gain of catalytic residue at Q378 (P = 0.0223);
MVP
MPC
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
Name
Calibrated prediction
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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