Submissions for variant NM_000527.5(LDLR):c.2479G>A (p.Val827Ile)

dbSNP: rs137853964

Total submissions: 33

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	RCV000030135	SCV001960944	uncertain significance	Hypercholesterolemia, familial, 1	2021-06-22	reviewed by expert panel	curation	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.
LDLR-LOVD, British Heart Foundation	RCV000030135	SCV000296021	likely benign	Hypercholesterolemia, familial, 1	2016-03-25	criteria provided, single submitter	literature only
Robarts Research Institute, Western University	RCV000030135	SCV000484685	likely benign	Hypercholesterolemia, familial, 1	2019-08-22	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	RCV000030135	SCV000503493	benign	Hypercholesterolemia, familial, 1	2016-12-16	criteria provided, single submitter	clinical testing	subjects mutated among 2600 FH index cases screened = 10 , family member = 1/previously described in association with FH/Software predictions: Conflicting
GeneDx	RCV000058923	SCV000521002	uncertain significance	not provided	2023-06-16	criteria provided, single submitter	clinical testing	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)
Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation	RCV000030135	SCV000540872	uncertain significance	Hypercholesterolemia, familial, 1	2016-11-05	criteria provided, single submitter	clinical testing	Probably not pathogenic - position 827 in NPXY signal is variable - PMID: 1968060
Invitae	RCV001079897	SCV000556789	likely benign	Familial hypercholesterolemia	2024-01-31	criteria provided, single submitter	clinical testing
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille	RCV000030135	SCV000583958	likely pathogenic	Hypercholesterolemia, familial, 1	2017-03-30	criteria provided, single submitter	clinical testing
Laboratory of Genetics and Molecular Cardiology, University of São Paulo	RCV000030135	SCV000588668	uncertain significance	Hypercholesterolemia, familial, 1	2016-03-01	criteria provided, single submitter	research
Phosphorus, Inc.	RCV000030135	SCV000679811	uncertain significance	Hypercholesterolemia, familial, 1	2017-08-01	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000030135	SCV000689777	benign	Hypercholesterolemia, familial, 1	2017-08-29	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000855648	SCV000697231	likely benign	not specified	2024-01-16	criteria provided, single submitter	clinical testing	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.
Department of Human Genetics, Laborarztpraxis Dres. Walther, Weindel und Kollegen	RCV000030135	SCV000987030	uncertain significance	Hypercholesterolemia, familial, 1	2018-07-24	criteria provided, single submitter	clinical testing	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
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000058923	SCV001134262	benign	not provided	2019-05-15	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000030135	SCV001286499	uncertain significance	Hypercholesterolemia, familial, 1	2017-04-27	criteria provided, single submitter	clinical testing	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.
Brunham Lab, Centre for Heart and Lung Innovation, University of British Columbia	RCV000030135	SCV001432640	likely pathogenic	Hypercholesterolemia, familial, 1	2019-01-27	criteria provided, single submitter	research
Laboratory of Human Genetics, Universidade de São Paulo	RCV000030135	SCV001438313	pathogenic	Hypercholesterolemia, familial, 1	2020-10-19	criteria provided, single submitter	research
Genome-Nilou Lab	RCV000030135	SCV001737274	uncertain significance	Hypercholesterolemia, familial, 1	2021-06-10	criteria provided, single submitter	clinical testing
Laboratory of Medical Genetics, National & Kapodistrian University of Athens	RCV000030135	SCV002577501	uncertain significance	Hypercholesterolemia, familial, 1	2022-05-05	criteria provided, single submitter	clinical testing	PM2, PP2, PP3
Ambry Genetics	RCV002453272	SCV002737499	benign	Cardiovascular phenotype	2018-02-22	criteria provided, single submitter	clinical testing	This alteration is classified as benign based on a combination of the following: 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.
New York Genome Center	RCV000030135	SCV002764415	uncertain significance	Hypercholesterolemia, familial, 1	2023-04-03	criteria provided, single submitter	clinical testing	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.
Fulgent Genetics, Fulgent Genetics	RCV000030135	SCV002780050	uncertain significance	Hypercholesterolemia, familial, 1	2022-04-20	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000058923	SCV004564328	uncertain significance	not provided	2023-01-26	criteria provided, single submitter	clinical testing	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.
CeGaT Center for Human Genetics Tuebingen	RCV000058923	SCV004699673	likely benign	not provided	2024-03-01	criteria provided, single submitter	clinical testing	LDLR: PM5, BS2
SNPedia	RCV000058923	SCV000090444	not provided	not provided		no assertion provided	not provided
Dept. of Genetics and Pharmacogenomics, Merck Research Labs	RCV000058923	SCV000189592	not provided	not provided		no assertion provided	in vitro
CSER _CC_NCGL, University of Washington	RCV002051648	SCV000190299	uncertain significance	Hypercholesterolemia	2014-06-01	no assertion criteria provided	research
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	RCV000030135	SCV000606661	benign	Hypercholesterolemia, familial, 1		no assertion criteria provided	research
GenomeConnect, ClinGen	RCV000030135	SCV000840216	not provided	Hypercholesterolemia, familial, 1		no assertion provided	phenotyping only	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.
Natera, Inc.	RCV001079897	SCV001453903	likely benign	Familial hypercholesterolemia	2020-01-12	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000058923	SCV001553547	uncertain significance	not provided		no assertion criteria provided	clinical testing	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.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000058923	SCV001740154	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000855648	SCV001925900	benign	not specified		no assertion criteria provided	clinical testing