rs137853964

chr19-11129602-G-Achr19-11129602-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PP3 PP1

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
• Clinical Significance: Uncertain significance reviewed by expert panel P:3 U:14 B:13 O:3
• 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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LDLR	NM_000527.5	c.2479G>A	p.Val827Ile	missense_variant	17/18	ENST00000558518.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LDLR	ENST00000558518.6	c.2479G>A	p.Val827Ile	missense_variant	17/18	1	NM_000527.5	P3

Frequencies

GnomAD3 genomes AF: 0.000461 AC: 70 AN: 151924 Hom.: 0 Cov.: 31

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

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

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

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:3 Uncertain:14 Benign:13 Other:3

Revision: reviewed by expert panel

Submissions by phenotype

Hypercholesterolemia, familial, 1 Pathogenic:3 Uncertain:10 Benign:5 Other:1

Likely benign, criteria provided, single submitter	literature only	LDLR-LOVD, British Heart Foundation	Mar 25, 2016	- -
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, 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. -
Pathogenic, criteria provided, single submitter	research	Laboratory of Human Genetics, Universidade de São Paulo	Oct 19, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Phosphorus, Inc.	Aug 01, 2017	- -
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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Apr 20, 2022	- -
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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory of Medical Genetics, National & Kapodistrian University of Athens	May 05, 2022	PM2, PP2, PP3 -
Benign, no assertion criteria provided	research	Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Robarts Research Institute, Western University	Aug 22, 2019	- -
Uncertain significance, criteria provided, single submitter	research	Laboratory of Genetics and Molecular Cardiology, University of São Paulo	Mar 01, 2016	- -
Likely pathogenic, criteria provided, single submitter	research	Brunham Lab, Centre for Heart and Lung Innovation, University of British Columbia	Jan 27, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jun 10, 2021	- -
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 -
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. -
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 -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Aug 29, 2017	- -

not provided Uncertain:3 Benign:3 Other:2

not provided, no classification provided	in vitro	Dept. of Genetics and Pharmacogenomics, Merck Research Labs	-	- -
not provided, no classification provided	literature only	SNPedia	-	- -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	May 15, 2019	- -
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. -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
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. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jun 16, 2023	Reported 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) -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2024	LDLR: PM5, BS2 -

not specified Benign:2

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. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

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	Invitae	Jan 31, 2024	- -

Hypercholesterolemia Uncertain:1

Uncertain significance, no assertion criteria provided

research

CSER _CC_NCGL, University of Washington

Jun 01, 2014

- -

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: 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

Other links and lift over

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