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rs137853964

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PM1PM5BP4_Strong

The NM_000527.5(LDLR):c.2479G>A(p.Val827Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000558 in 1,613,892 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V827D) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00046 ( 0 hom., cov: 31)
Exomes 𝑓: 0.00057 ( 4 hom. )

Consequence

LDLR
NM_000527.5 missense

Scores

4
10
4

Clinical Significance

Uncertain significance reviewed by expert panel P:3U:14B:13O:3

Conservation

PhyloP100: 9.77
Variant links:
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 0 ACMG points.

PM1
In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_000527.5
PM5
Other missense variant is known to change same aminoacid residue: Variant chr19-11129602-G-T is described in ClinVar as [Uncertain_significance]. Clinvar id is 375840.Status of the report is reviewed_by_expert_panel, 3 stars. We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, Uncertain_significance=3}.
BP4
Computational evidence support a benign effect (MetaRNN=0.012337297).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
LDLRNM_000527.5 linkuse as main transcriptc.2479G>A p.Val827Ile missense_variant 17/18 ENST00000558518.6

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
LDLRENST00000558518.6 linkuse as main transcriptc.2479G>A p.Val827Ile missense_variant 17/181 NM_000527.5 P3P01130-1

Frequencies

GnomAD3 genomes
AF:
0.000461
AC:
70
AN:
151924
Hom.:
0
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.0000242
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000197
Gnomad ASJ
AF:
0.0144
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000206
Gnomad OTH
AF:
0.000959
GnomAD3 exomes
AF:
0.00101
AC:
253
AN:
251460
Hom.:
1
AF XY:
0.000964
AC XY:
131
AN XY:
135914
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00104
Gnomad ASJ exome
AF:
0.0167
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000316
Gnomad OTH exome
AF:
0.00212
GnomAD4 exome
AF:
0.000568
AC:
830
AN:
1461850
Hom.:
4
Cov.:
32
AF XY:
0.000568
AC XY:
413
AN XY:
727228
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.00110
Gnomad4 ASJ exome
AF:
0.0189
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.000162
Gnomad4 OTH exome
AF:
0.00174
GnomAD4 genome
AF:
0.000460
AC:
70
AN:
152042
Hom.:
0
Cov.:
31
AF XY:
0.000390
AC XY:
29
AN XY:
74302
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.000197
Gnomad4 ASJ
AF:
0.0144
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000206
Gnomad4 OTH
AF:
0.000949
Alfa
AF:
0.00136
Hom.:
0
Bravo
AF:
0.000665
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.00116
AC:
10
ExAC
AF:
0.000758
AC:
92
EpiCase
AF:
0.000218
EpiControl
AF:
0.000593

ClinVar

Significance: Uncertain significance
Submissions summary: Pathogenic:3Uncertain:14Benign:13Other:3
Revision: reviewed by expert panel
LINK: link

Submissions by phenotype

Hypercholesterolemia, familial, 1 Pathogenic:3Uncertain:10Benign:5Other:1
Benign, criteria provided, single submitterclinical testingColor Diagnostics, LLC DBA Color HealthAug 29, 2017- -
not provided, no classification providedphenotyping onlyGenomeConnect, 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. -
Likely benign, criteria provided, single submitterclinical testingRobarts Research Institute, Western UniversityAug 22, 2019- -
Uncertain significance, criteria provided, single submitterclinical testingLaboratory of Medical Genetics, National & Kapodistrian University of AthensMay 05, 2022PM2, PP2, PP3 -
Benign, criteria provided, single submitterclinical testingCentre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-FoixDec 16, 2016subjects 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 submitterclinical testingDepartment of Human Genetics, Laborarztpraxis Dres. Walther, Weindel und KollegenJul 24, 2018This 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 submitterclinical testingFulgent Genetics, Fulgent GeneticsApr 20, 2022- -
Uncertain significance, criteria provided, single submitterclinical testingNew York Genome CenterApr 03, 2023The 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. -
Benign, no assertion criteria providedresearchLaboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum-- -
Uncertain significance, criteria provided, single submitterclinical testingMolecular Genetics Laboratory, Centre for Cardiovascular Surgery and TransplantationNov 05, 2016Probably not pathogenic - position 827 in NPXY signal is variable - PMID: 1968060 -
Likely pathogenic, criteria provided, single submitterclinical testingU4M - Lille University & CHRU Lille, Université de Lille - CHRU de LilleMar 30, 2017- -
Uncertain significance, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaApr 27, 2017This 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. -
Uncertain significance, criteria provided, single submitterclinical testingPhosphorus, Inc.Aug 01, 2017- -
Likely pathogenic, criteria provided, single submitterresearchBrunham Lab, Centre for Heart and Lung Innovation, University of British ColumbiaJan 27, 2019- -
Likely benign, criteria provided, single submitterliterature onlyLDLR-LOVD, British Heart FoundationMar 25, 2016- -
Pathogenic, criteria provided, single submitterresearchLaboratory of Human Genetics, Universidade de São PauloOct 19, 2020- -
Uncertain significance, criteria provided, single submitterclinical testingGenome-Nilou LabJun 10, 2021- -
Uncertain significance, criteria provided, single submitterresearchLaboratory of Genetics and Molecular Cardiology, University of São PauloMar 01, 2016- -
Uncertain significance, reviewed by expert panelcurationClinGen Familial Hypercholesterolemia Variant Curation Expert PanelJun 22, 2021NM_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. -
not provided Uncertain:3Benign:3Other:2
Uncertain significance, criteria provided, single submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesJan 26, 2023The 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. -
Uncertain significance, criteria provided, single submitterclinical testingGeneDxJun 16, 2023Reported multiple times in association with familial hypercholesterolemia (FH) and early onset myocardial infarction (MI); however, there are conflicting conclusions with regard to pathogenicity and this variant has also been reported in healthy control cohorts, in individuals with normal LDL-C levels, and in affected individuals who also harbor additional FH-related variants (Hobbs et al., 1992; Lombardi et al., 2000; Zakharova et al., 2005; Huijgen et al., 2010; Tichy et al., 2012; Gonzalez-Garay et al., 2013; Bertolini et al., 2013; Vandrovcova et al., 2013; Freudenberg-Hua et al., 2014; Lange et al., 2014; Norsworthy et al., 2014; Thormaehlen et al., 2015; Do et al., 2015; Durst et al., 2017; Sun et al., 2018; Dron et al., 2020; Gill et al., 2021; Meshkov et al., 2021); 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, 28104544, 27765764, 22294733, 19843101, 18400033, 15823288, 15199436, 11462246, 33418990, 34834584, 32719484, 35339733, 1301956, 33303402, 32041611, 33079599, 33508743, 32423031, 27824480, 31345425, 29874871, 27050191, 24503134, 23054246, 19026292, 11810272, 26802169, 19602640, 21310417) -
Benign, criteria provided, single submitterclinical testingQuest Diagnostics Nichols Institute San Juan CapistranoMay 15, 2019- -
Likely benign, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenMar 01, 2024LDLR: PM5, BS2 -
not provided, no classification providedliterature onlySNPedia-- -
not provided, no classification providedin vitroDept. of Genetics and Pharmacogenomics, Merck Research Labs-- -
Likely benign, no assertion criteria providedclinical testingDiagnostic Laboratory, Department of Genetics, University Medical Center Groningen-- -
Uncertain significance, no assertion criteria providedclinical testingDepartment 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. -
not specified Benign:2
Likely benign, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpJan 16, 2024Variant 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. -
Benign, no assertion criteria providedclinical testingClinical Genetics, Academic Medical Center-- -
Familial hypercholesterolemia Benign:2
Likely benign, criteria provided, single submitterclinical testingInvitaeJan 31, 2024- -
Likely benign, no assertion criteria providedclinical testingNatera, Inc.Jan 12, 2020- -
Hypercholesterolemia Uncertain:1
Uncertain significance, no assertion criteria providedresearchCSER _CC_NCGL, University of WashingtonJun 01, 2014- -
Cardiovascular phenotype Benign:1
Benign, criteria provided, single submitterclinical testingAmbry GeneticsFeb 22, 2018This 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: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.10
BayesDel_addAF
Uncertain
0.13
D
BayesDel_noAF
Pathogenic
0.36
Cadd
Pathogenic
28
Dann
Uncertain
1.0
DEOGEN2
Uncertain
0.54
D;.;.;.;.
Eigen
Pathogenic
0.72
Eigen_PC
Uncertain
0.65
FATHMM_MKL
Uncertain
0.97
D
LIST_S2
Pathogenic
1.0
D;D;D;D;D
M_CAP
Uncertain
0.21
D
MetaRNN
Benign
0.012
T;T;T;T;T
MetaSVM
Pathogenic
0.92
D
MutationAssessor
Uncertain
2.5
M;.;.;.;M
MutationTaster
Benign
1.0
D;D;D;D;D;D;D
PrimateAI
Uncertain
0.73
T
PROVEAN
Benign
-0.89
N;N;N;N;N
Sift
Uncertain
0.027
D;D;D;D;T
Sift4G
Uncertain
0.022
D;D;D;D;D
Polyphen
1.0
D;.;.;.;.
Vest4
0.40
MVP
0.99
MPC
0.73
ClinPred
0.094
T
GERP RS
4.8
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.37
gMVP
0.90

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs137853964; hg19: chr19-11240278; COSMIC: COSV52944529; COSMIC: COSV52944529; API