ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.1027G>A (p.Gly343Ser)

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Total submissions: 18
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
LDLR-LOVD, British Heart Foundation RCV000211596 SCV000295150 likely pathogenic Familial hypercholesterolemia 1 2016-03-25 criteria provided, single submitter literature only
Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge RCV000211596 SCV000322922 uncertain significance Familial hypercholesterolemia 1 2016-03-01 criteria provided, single submitter research 0/190 non-FH alleles; 0/200 Brazilian (european ancestry) normolipidemic individuals
Robarts Research Institute,Western University RCV000211596 SCV000484753 likely pathogenic Familial hypercholesterolemia 1 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 RCV000211596 SCV000503283 likely pathogenic Familial hypercholesterolemia 1 2016-12-16 criteria provided, single submitter clinical testing subjects mutated among 2600 FH index cases screened = 7 , family members = 12 with co-segregation (1 homozygote in a family) / FH-Picardie, 15 to 30% LDLR activity / Software predictions: Damaging
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille RCV000211596 SCV000583777 pathogenic Familial hypercholesterolemia 1 2017-03-30 criteria provided, single submitter clinical testing
Laboratory of Genetics and Molecular Cardiology, University of São Paulo RCV000211596 SCV000588541 uncertain significance Familial hypercholesterolemia 1 2016-03-01 criteria provided, single submitter research
Fundacion Hipercolesterolemia Familiar RCV000211596 SCV000607546 uncertain significance Familial hypercholesterolemia 1 2016-03-01 criteria provided, single submitter research
GeneDx RCV000161977 SCV000617505 likely pathogenic not provided 2017-10-05 criteria provided, single submitter clinical testing The G343S likely pathogenic variant in the LDLR gene (previously reported as G322S and FH Picardie due to the use of alternate nomenclature) has been reported in association with FH across multiple ethnic groups (Reshef et al., 1996; Thiart et al., 2000; Fouchier et al., 2001; Salazar et al., 2002; Bourbon et al., 2008; Junyent et al., 2008; van der Graaf et al., 2011; Kusters et al., 2013; Medeiros et al., 2014; Jannes et al., 2015; Reiman et al., 2016; Sanchez-Hernandez et al., 2016; Gabcova et al., 2016). This variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). The G343S variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Furthermore, functional studies showed decreased LDL receptor activity (Hobbs et al., 1992). Missense variants in the same residue (G343V, G343D, G343C) have been reported in the Human Gene Mutation Database in association with FH (Stenson et al., 2014); however, the pathogenicity of these variants has not been definitively determined.
Integrated Genetics/Laboratory Corporation of America RCV000587327 SCV000697181 pathogenic Familial hypercholesterolemia 2017-05-09 criteria provided, single submitter clinical testing Variant summary: The LDLR c.1027G>A (p.Gly343Ser) variant involves the alteration of a conserved nucleotide, resulting in a missense substitution that lies within the EGF-like calcium-binding domain, the EGF-like domain, and the Growth factor receptor cysteine-rich domain (InterPro). 5/5 in silico tools predict a damaging outcome for this variant. This variant was found in the large control database ExAC at a frequency of 0.0000246 (3/121826 control chromosomes), which does not exceed the estimated maximal expected allele frequency of a pathogenic LDLR variant (0.0012508). The variant is present in patient cohorts affected with familial hypercholesterolemia (e.g., Bertolini_Arthero_2013; Salazar_HM_2002; Huijgen_HM_2010 amongst others) and is widely considered to be a pathogenic mutation in the literature. A functional study showed that the variant causes a ~50% reduction in LDL receptor protein at the cell surface likely due to protein misfolding, though the receptor that is present at the cell surface is able to bind and release LDL cholesterol properly (Boswell_JBC_2004). In addition, 2 other missense mutations at the Gly343 residue have been identified in patients with familial hypercholesterolemia (p.Gly343Cys [Jelassi_Artherosclerosis_2008] and p.Gly343Asp [Amsellem_HG_2002]), suggesting the residue is a critical amino acid in the development of hypercholesterolemia. Multiple clinical diagnostic laboratories/reputable databases have classified this variant with conflicting interpretations in ClinVar, including uncertain significance, likely pathogenic, and pathogenic. Taken together, this variant is classified as pathogenic.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000844735 SCV000712222 pathogenic Homozygous familial hypercholesterolemia 2019-03-11 criteria provided, single submitter clinical testing The p.Gly343Ser variant in LDLR (also described as p.Gly332Ser in the literature) has been reported across multiple ethnic groups in numerous individuals with familial hypercholesterolemia (FH). Most reports in patient cohorts were in the heterozygous state, with 2 compound heterozygous and 1 homozygous reports respectively (Hobbs 1992, Reshef 1996, Thiart 2000, Van Gaal 2001, Fouchier 2001, Salazar 2002, Mozas 2004, Junyent 2008, Bourbon 2008, Guardamagna 2009, Huijgen 2010, Hollants 2012, Bertolini 2013, Jannes 2015, Wang 2016, Sánchez-Hernández 2016, Gabčová 2017, ClinVar: submission accessions SCV000503283.1, SCV000583777.1 and SCV000268593.1). This variant segregated with disease in at least 4 affected family members from 3 families (Bourbon 2008, Bertolini 2013, Gabčová 2017). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID 183106). In vitro functional studies provide some evidence that the p.Gly343Ser variant affects protein folding and expression at the cell surface and results in decreased LDL receptor activity (Hobbs 1992; Boswell 2004). This variant has also been identified in 5/126,580 European chromosomes by gnomAD (http://gnomad.broadinstitute.org/). This frequency is low enough to be consistent with the frequency of FH in the general population. Computational prediction tools and conservation analysis suggest that the p.Gly343Ser variant may impact the protein. In addition, 3 other missense variants at this codon (p.Gly343Asp, p.Gly343Val, pGly343Cys) have been identified in patients with FH (Stenson 2017), suggesting that changes at this position are not tolerated. In summary, the p.Gly343Ser variant meets criteria to be classified as pathogenic for FH in an autosomal dominant manner based upon presence in multiple affected individuals, segregation studies, low frequency in controls, and functional and computational evidence. ACMG/AMP Criteria applied: PS4, PM2, PP3, PS3_supporting, PP1_Moderate.
Iberoamerican FH Network RCV000211596 SCV000748094 uncertain significance Familial hypercholesterolemia 1 2016-03-01 criteria provided, single submitter research
Invitae RCV000587327 SCV000821038 pathogenic Familial hypercholesterolemia 2019-12-16 criteria provided, single submitter clinical testing This sequence change replaces glycine with serine at codon 343 of the LDLR protein (p.Gly343Ser). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and serine. This variant is present in population databases (rs730882096, ExAC 0.005%). This variant has been reported in numerous individuals affected with familial hypercholesterolemia (PMID: 1301956, 11040093, 11933210, 20506408, 23375686, 22294733, 18096825, 17765246, 15241806, 25461735, 27765764). This variant is also known as G322S or FH-Picardie in the literature. ClinVar contains an entry for this variant (Variation ID: 183106). This variant has been reported to affect LDLR protein function (PMID: 15100232). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. This variant disrupts the p.Gly343 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been observed in individuals with LDLR-related conditions (PMID: 12436241, 18718593), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000161977 SCV001134244 pathogenic not provided 2018-12-11 criteria provided, single submitter clinical testing The best available variant frequency is uninformative because it is below the disease allele frequency. Statistically enriched in patients compared to controls. Predicted to have a damaging effect on the protein. The gain of a new splice site is predicted. Assessment of experimental evidence suggests this variant results in abnormal protein function.
Color RCV000587327 SCV001344025 pathogenic Familial hypercholesterolemia 2020-02-20 criteria provided, single submitter clinical testing
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute RCV000161977 SCV001433407 pathogenic not provided 2019-08-02 criteria provided, single submitter clinical testing
Dept. of Genetics and Pharmacogenomics, Merck Research Labs RCV000161977 SCV000189552 not provided not provided no assertion provided in vitro
Cardiovascular Genetics Laboratory,PathWest Laboratory Medicine WA - Fiona Stanley Hospital RCV000211596 SCV000268593 pathogenic Familial hypercholesterolemia 1 2008-06-09 no assertion criteria provided clinical testing
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde,Academisch Medisch Centrum RCV000211596 SCV000606295 pathogenic Familial hypercholesterolemia 1 no assertion criteria provided research

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