rs137853964
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Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PP3PP1
This summary comes from the ClinGen Evidence Repository: NM_000527.5(LDLR):c.2479G>A (p.Val827Ile) variant is classified as variant of Uncertain significance for Familial Hypercholesterolemia by applying evidence codes (PP1 and PP3) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755). The supporting evidence is as follows: PP1 - Variant segregates with FH phenotype in 3 informative meiosis from Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation).PP3 - REVEL: 0,771. Score is above 0,75. LINK:https://erepo.genome.network/evrepo/ui/classification/CA023677/MONDO:0007750/013
Frequency
Genomes: 𝑓 0.00046 ( 0 hom., cov: 31)
Exomes 𝑓: 0.00057 ( 4 hom. )
Consequence
LDLR
NM_000527.5 missense
NM_000527.5 missense
Scores
5
10
4
Clinical Significance
Conservation
PhyloP100: 9.77
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 Uncertain_significance. Variant got 2 ACMG points.
PP1
For more information check the summary or visit ClinGen Evidence Repository.
PP3
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.2479G>A | p.Val827Ile | missense_variant | 17/18 | ENST00000558518.6 | NP_000518.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| LDLR | ENST00000558518.6 | c.2479G>A | p.Val827Ile | missense_variant | 17/18 | 1 | NM_000527.5 | ENSP00000454071 | P3 |
Frequencies
GnomAD3 genomes 0.000461 AC: 70AN: 151924Hom.: 0 Cov.: 31
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GnomAD3 exomes AF: 0.00101 AC: 253AN: 251460Hom.: 1 AF XY: 0.000964 AC XY: 131AN XY: 135914
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GnomAD4 exome AF: 0.000568 AC: 830AN: 1461850Hom.: 4 Cov.: 32 AF XY: 0.000568 AC XY: 413AN XY: 727228
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GnomAD4 genome 0.000460 AC: 70AN: 152042Hom.: 0 Cov.: 31 AF XY: 0.000390 AC XY: 29AN XY: 74302
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ClinVar
Significance: Uncertain significance
Submissions summary: Pathogenic:3Uncertain:15Benign:13Other:3
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
Hypercholesterolemia, familial, 1 Pathogenic:3Uncertain:10Benign:5Other:1
| Pathogenic, criteria provided, single submitter | research | Laboratory of Human Genetics, Universidade de São Paulo | Oct 19, 2020 | - - |
| Likely pathogenic, criteria provided, single submitter | research | Brunham Lab, Centre for Heart and Lung Innovation, University of British Columbia | Jan 27, 2019 | - - |
| Uncertain significance, reviewed by expert panel | curation | ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel | Jun 22, 2021 | NM_000527.5(LDLR):c.2479G>A (p.Val827Ile) variant is classified as variant of Uncertain significance for Familial Hypercholesterolemia by applying evidence codes (PP1 and PP3) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755). The supporting evidence is as follows: PP1 - Variant segregates with FH phenotype in 3 informative meiosis from Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation). PP3 - REVEL: 0,771. Score is above 0,75. - |
| Likely benign, criteria provided, single submitter | literature only | LDLR-LOVD, British Heart Foundation | Mar 25, 2016 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory of Medical Genetics, National & Kapodistrian University of Athens | May 05, 2022 | PM2, PP2, PP3 - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Jun 10, 2021 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | New York Genome Center | Apr 03, 2023 | The c.2479G>A variant identified in LDLR has previously been reported in individuals with familial hypercholesterolemia [PMID:1301956,19026292,23680767, 15701167, 28104544, 31106297, 32423031, 33079599, 33418990, 23669246] and it has been classified as variant of uncertain significance for familial hypercholesterolemia by ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel [ClinVar ID: 36462]. The c.2479G>A variant is observed in 446 alleles (~0.08% minor allele frequency with 1 homozygote) in population databases (gnomAD v2.1.1 and v3.1.2, TOPMed Freeze 8) with ~1.5% minor allele frequency in individuals of Ashkenazi Jewish ancestry. The c.2479G>A variant is located in exon 17 of this 18-exon gene and predicted to replace an evolutionarily conservedvaline amino acid with isoleucine at position 827 (p.(Val827Ile)) within the NPXY motif (aa 823-828) in cytoplasmic tail of LDLR that is critical for internalization of receptors into clathrin-coated pits [PMID: 21144047; UniProtKB ID:P01130]. In silico algorithms provide supporting prediction for damaging effect of the variant (CADDv1.6= 26.3; REVEL= 0.771); however, this was not supported by in vitro cell-based functional characterization studies on LDL-uptake [PMID: 25647241]. Based on available evidence this heterozygous c.2479G>A p.(Val827Ile) variant identified in LDLR is reported as a Variant of uncertain significance. - |
| Likely benign, criteria provided, single submitter | clinical testing | Robarts Research Institute, Western University | Aug 22, 2019 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Apr 20, 2022 | - - |
| Benign, no assertion criteria provided | research | Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum | - | - - |
| Uncertain significance, criteria provided, single submitter | research | Laboratory of Genetics and Molecular Cardiology, University of São Paulo | Mar 01, 2016 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Phosphorus, Inc. | Aug 01, 2017 | - - |
| not provided, no classification provided | phenotyping only | GenomeConnect, ClinGen | - | GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. - |
| Benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Aug 29, 2017 | - - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille | Mar 30, 2017 | - - |
| Benign, 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 = 10 , family member = 1/previously described in association with FH/Software predictions: Conflicting - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation | Nov 05, 2016 | Probably not pathogenic - position 827 in NPXY signal is variable - PMID: 1968060 - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Department of Human Genetics, Laborarztpraxis Dres. Walther, Weindel und Kollegen | Jul 24, 2018 | This nucleotide substitution c.2479G>A causes an exchange of the amino acid valine for isoleucine at position 827 (p.Val827Ile). This rare variant is known in the literature as the "FH New York-5" variant and is discussed in the context of hypercholesterolemia. The pathogenicity of this gene change is assessed differently in the literature and databases and must therefore be classified as a variant of unclear clinical significance (VUS, class 3). In the first description, it was described as a disease-causing mutation and later classified as a polymorphism. This variant was found both in FH patients and in the control group. An influence of the amino acid exchange on the LDL receptor activity could not be detected so far. We observed this mutation in a patient without the classical criteria for FADH. In this case a slightly elevated TC was combined with normal LDL-C but signicantly elevated TG (up to 400 mg/dl). PMID: 1301956, 25647241, 28104544, 23680767 - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
not provided Uncertain:3Benign:3Other:2
| not provided, no classification provided | in vitro | Dept. of Genetics and Pharmacogenomics, Merck Research Labs | - | - - |
| Uncertain significance, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The LDLR p.Val786Ile variant was identified in 11 of 1248 proband chromosomes (frequency: 0.0088) from individuals or families with familial hypercholesterolemia (FH) or high cholesterol (Durst_2017_PMID:28104544; Norsworthy_2014_PMID:24956927; Vandrovcova_2013_PMID:23680767; Futema_2012_PMID:23054246). The variant was also identified in dbSNP (ID: rs137853964), LOVD 3.0 and in ClinVar (classified as benign 3 times, likely benign twice, likely pathogenic twice and as a VUS 7 times). The variant was not identified in Cosmic. The variant was identified in control databases in 260 of 282820 chromosomes (1 homozygous) at a frequency of 0.000919 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Ashkenazi Jewish in 171 of 10370 chromosomes (freq: 0.01649), Other in 13 of 7216 chromosomes (freq: 0.001802), Latino in 37 of 35440 chromosomes (freq: 0.001044) and European (non-Finnish) in 39 of 129164 chromosomes (freq: 0.000302), while the variant was not observed in the African, East Asian, European (Finnish), and South Asian populations. The variant was identified in 8/67 patients with FH but was found not to be sufficient on its own to cause FH as it was found in combination with risk SNPs or in the compound heterozygous state (Durst_2017_PMID:28104544). The V786I variant was identified in 1/84 patients with FH but was also identified in the patient's unaffected daughter (Vandrovcova_2013_PMID:23680767). The p.Val786 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Aug 26, 2024 | In silico analysis supports that this missense variant does not alter protein structure/function; Also known as p.(V806I) and FH New York-5; This variant is associated with the following publications: (PMID: 24507775, 23375686, 25637381, 20506408, 25333069, 22698793, 24956927, 24055113, 22390909, 23680767, 25487149, 24082139, 26332594, 15701167, 10735632, 25647241, 27044878, 31106297, 32629184, 31153847, 31624327, 27765764, 22294733, 19843101, 18400033, 15823288, 15199436, 11462246, 33418990, 34834584, 32719484, 35339733, 33303402, 32041611, 33079599, 33508743, 32423031, 27824480, 31345425, 29874871, 27050191, 24503134, 23054246, 19026292, 11810272, 26802169, 19602640, 21310417, 1301956, 28104544, 34756585, 35460704) - |
| not provided, no classification provided | literature only | SNPedia | - | - - |
| Likely benign, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
| Benign, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | May 15, 2019 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Jan 26, 2023 | The LDLR c.2479G>A; p.Val827Ile variant (rs137853964) is reported in the literature in individuals affected with familial hypercholesterolemia (Bertolini 2013, Durst 2017, Hobbs 1992, Noto 2022, Sun 2018) but is also found in healthy controls (Do 2015, Thormaehlen 2015). This variant is also reported in ClinVar (Variation ID: 36462). This variant is found in the Ashkenazi Jewish population with an allele frequency of 1.6% (171/10370 alleles, including 1 homozygote) in the Genome Aggregation database. Computational analyses predict that this variant is deleterious (REVEL: 0.771). However, functional analyses of the variant protein show no effect on LDL uptake (Thormaehlen 2015). Due to conflicting information, the clinical significance of the p.Val827Ile variant is uncertain at this time. References: Bertolini S et al. Spectrum of mutations and phenotypic expression in patients with autosomal dominant hypercholesterolemia identified in Italy. Atherosclerosis. 2013 Apr;227(2):342-8. PMID: 23375686. Do R et al. Exome sequencing identifies rare LDLR and APOA5 alleles conferring risk for myocardial infarction. Nature. 2015 Feb 5;518(7537):102-6. PMID: 25487149. Durst R et al. Molecular genetics of familial hypercholesterolemia in Israel-revisited. Atherosclerosis. 2017 Feb;257:55-63. PMID: 28104544. Hobbs HH et al. Molecular genetics of the LDL receptor gene in familial hypercholesterolemia. Hum Mutat. 1992;1(6):445-66. PMID: 1301956. Noto D et al. Diagnosis of familial hypercholesterolemia in a large cohort of Italian genotyped hypercholesterolemic patients. Atherosclerosis. 2022 Apr;347:63-67. PMID: 35339733. Sun YV et al. Effects of Genetic Variants Associated with Familial Hypercholesterolemia on Low-Density Lipoprotein-Cholesterol Levels and Cardiovascular Outcomes in the Million Veteran Program. Circ Genom Precis Med. 2018 Dec;11(12):e002192. PMID: 31106297. Thormaehlen AS et al. Systematic cell-based phenotyping of missense alleles empowers rare variant association studies: a case for LDLR and myocardial infarction. PLoS Genet. 2015 Feb 3;11(2):e1004855. PMID: 25647241. - |
| Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Aug 01, 2024 | LDLR: PM5, BS2 - |
not specified Benign:2
| Benign, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
| Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jan 16, 2024 | Variant summary: LDLR c.2479G>A (p.Val827Ile) results in a 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 0.00056 in 1616456 control chromosomes, predominantly at a frequency of 0.018 within the Ashkenazi Jewish subpopulation in the gnomAD database, including 3 homozygotes. The observed variant frequency within Ashkenazi Jewish control individuals in the gnomAD database is approximately 14.39 fold of the estimated maximal expected allele frequency for a pathogenic variant in LDLR causing Familial Hypercholesterolemia phenotype (0.0013), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Ashkenazi Jewish origin. c.2479G>A has been reported in the literature in compound heterozygous and homozygous individuals affected with Familial Hypercholesterolemia (Hobbs_1992, Kolansky_2008, Vandrovcova_2013, Zakharova_2005, Durst_2016, Sun_2018, Semenova_2020, Trinder_2020, Meshkov_2021, Futema_2021). In addition, the variant did not segregate with disease in one family (Vandrovcova_2013). Since the penetrance of Familial Hypercholesterolemia (0.75) due to this variant appears to be lower than expected (0.8), no conclusions can be drawn from these data. Co-occurrences with other pathogenic variants have been reported (LDLR c.651_653TGG, p.Gly219del; LDLR c.418G>A, p.Glu140Lys; LDLR c.420G>T, p.Glu140Asp; LDLR c.1775G>A, p.Gly592Glu), providing supporting evidence for a benign role (Hobbs_1992, Kolansky_2008, Durst_2016, Semenova_2020). Hobb_1992 reports experimental evidence evaluating an impact on protein function, however, does not allow convincing conclusions about the variant effect. ClinVar contains an entry for this variant (Variation ID: 36462). Based on the evidence outlined above, the variant was classified as likely benign. - |
Familial hypercholesterolemia Benign:2
| Likely benign, no assertion criteria provided | clinical testing | Natera, Inc. | Jan 12, 2020 | - - |
| Likely benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 31, 2024 | - - |
Hypercholesterolemia Uncertain:1
| Uncertain significance, no assertion criteria provided | research | CSER _CC_NCGL, University of Washington | Jun 01, 2014 | - - |
LDLR-related disorder Uncertain:1
| Uncertain significance, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Mar 07, 2024 | The LDLR c.2479G>A variant is predicted to result in the amino acid substitution p.Val827Ile. This variant has been documented in many studies of familial hypercholesterolemia (FH), but to date results have been conflicting. Some studies report this variant to result in a mild form of FH (Hobbs et al. 1992. PubMed ID: 1301956; Durst et al. 2017. PubMed ID: 28104544), whilst others report this variant as non-pathogenic (Huijgen et al. 2010. PubMed ID: 20506408; Table 18, Do et al. 2015. PubMed ID: 25487149; Thormaehlen et al. 2015. PubMed ID: 25647241). This variant has been reported 260 times among ~283,000 alleles (~0.09%) in a large population database. It is enriched in the Ashkenazi Jewish subpopulation with an allele frequency of 1.66% and one homozygous finding. It has conflicting interpretations in ClinVar ranging from benign to uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/36462/). Although we suspect this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
Cardiovascular phenotype Benign:1
| Benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 22, 2018 | This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Uncertain
D;.;.;.;.
Eigen
Pathogenic
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Pathogenic
D;D;D;D;D
M_CAP
Uncertain
D
MetaRNN
Benign
T;T;T;T;T
MetaSVM
Pathogenic
D
MutationAssessor
Uncertain
M;.;.;.;M
MutationTaster
Benign
D;D;D;D;D;D;D
PrimateAI
Uncertain
T
PROVEAN
Benign
N;N;N;N;N
REVEL
Pathogenic
Sift
Uncertain
D;D;D;D;T
Sift4G
Uncertain
D;D;D;D;D
Polyphen
D;.;.;.;.
Vest4
MVP
MPC
ClinPred
T
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