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

Total submissions: 34

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	RCV000211596	SCV004022448	pathogenic	Hypercholesterolemia, familial, 1	2023-04-28	reviewed by expert panel	curation	The NM_000527.5 (LDLR):c.1027G>A (p.Gly343Ser) variant is classified as Pathogenic (modified) for Familial Hypercholesterolemia by applying evidence codes (PM2, PP3, PS3, PP4, PS4, PP1_Strong, PM5, PM3, BS4) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: PM2: PopMaxMAF=0.00005 in East Asian population from gnomAD (gnomAD v2.1.1). PP3: REVEL=0.929, it is above 0.75. PS3: Level 1 assays: PMID 15100232. Heterologous cells (CHO) were used in WB, FACS and NMR Spectroscopy. The experiments shown <60% cell surface LDLR expression (Fig 5C), and >80% expressed receptor bind and release LDL upon low pH condition (Fig 6B), the amount of LDL bound to the mutant receptor correlates tightly with cell-surface LDLR expression, NMR indicates misfolding defects of the receptor. Functional data is consistent with damaging effect. This study is reported by Boswell et al, 2004, from Department of Biochemistry, Division of Structural Biology, University of Oxford, UK. PP4: Variant meets PM2 and is identified in at least >1 index cases who fulfil criteria for FH after alternative causes of high cholesterol were excluded. PS4: Variant meets PM2 and is identified in at least 26 index cases reported in VCI and PubMed. There are 14 unrelated index case reported in VCI who fulfil criteria for FH diagnosis: Twelve cases fulfil DLCN criteria, 7 reported from Service de Biochimie et de Biologie Moléculaire, Hospices Civils de Lyon, Lyon, France, 1 from Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA), 2 from Research Lab of Molecular Genetics of Lipid Metabolism; and 2 from Robarts Research Institute, Canada; two cases fulfil Simon Broome possible criteria, reported from Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge. Variant is reported in PubMed in at least 12 index cases fulfil criteria for FH diagnosis: 8 cases fulfil DLCN probable/definite FH criteria in PMID 11040093, 11810272, 32977124, 30270055, 27784735; 1 case fulfil Simon Broome possible FH criteria in PMID 26748104; 3 cases fulfil MedPed criteria in PMID 8882879, 27824480. PP1_Strong: Variant segregates with FH phenotype in 18 informative meiosis from 6 families reported from 4 different labs in VCI: 11 affected carries and 7 unaffected non-carriers reported from Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA), Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge, Laboratory of Genetics and Molecular Cardiology, and Research Lab of Molecular Genetics of Lipid Metabolism. PM5: Three other variants at the same codon: NM_000527.5(LDLR):c.1028G>T (p.Gly343Val)(ClinVarID 440618) classified as Likely Pathogenic, NM_000527.5(LDLR):c.1028G>A (p.Gly343Asp)(ClinVarID 251606) is classified as Likely Pathogenic, NM_000527.5(LDLR):c.1027G>T (p.Gly343Cys)(ClinVarID 251605) is classified as Pathogenic, by these guidelines, therefore PM5 is met. PM3: Variant meets PM2 and is identified in an index case with homozygous FH phenotype (untreated LDL-C > 500mg/dL, or LDL-C > 300 mmol/dL on high-intensive lipid-lowering therapy and the presence of tendon xanthomas before 10 year of age), reported by Sanchez-Hernandez et al, 2016, Universitario Insular Materno Infantil de Gran Canaria, Spain, PMID 27784735. This variant met enough pathogenic criteria toward Pathogenic classification by these guidelines before PM3 code applied. BS4: Variant does not segregate with FH phenotype in total of 6 informative meiosis reported in VCI. Five affected relatives without the variant and had LDL-C>75th percentile, 2 cases from Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA), 1 case each from Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge, Laboratory of Genetics and Molecular Cardiology, and Research Lab of Molecular Genetics of Lipid Metabolism. There is 1 instance reported from 1 laboratory, where an unaffected family member had LDL-C<50th percentile and carries the variant, reported in VCI from Laboratory of Genetics and Molecular Cardiology, GTR LabID 505581. Variant has 3 Strong, 3 Moderate and 2 Supporting evidence codes toward Pathogenic, enough to classify as Pathogenic, and only 1 Strong evidence code towards Benign. The Pathogenic criteria overwhelms the Benign criteria, so we are confident in classifying this variant as Pathogenic.
LDLR-LOVD, British Heart Foundation	RCV000211596	SCV000295150	likely pathogenic	Hypercholesterolemia, familial, 1	2016-03-25	criteria provided, single submitter	literature only
Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge	RCV000211596	SCV000322922	uncertain significance	Hypercholesterolemia, familial, 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	Hypercholesterolemia, familial, 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	Hypercholesterolemia, familial, 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	Hypercholesterolemia, familial, 1	2017-03-30	criteria provided, single submitter	clinical testing
Laboratory of Genetics and Molecular Cardiology, University of São Paulo	RCV000211596	SCV000588541	uncertain significance	Hypercholesterolemia, familial, 1	2016-03-01	criteria provided, single submitter	research
Fundacion Hipercolesterolemia Familiar	RCV000211596	SCV000607546	uncertain significance	Hypercholesterolemia, familial, 1	2016-03-01	criteria provided, single submitter	research
GeneDx	RCV000161977	SCV000617505	pathogenic	not provided	2022-01-17	criteria provided, single submitter	clinical testing	Published functional studies demonstrate that this variant affects protein folding and cell surface expression, resulting in decreased LDL receptor activity (Hobbs et al., 1992; Boswell et al., 2004); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 11040093, 29353225, 11851376, 15241806, 18757057, 22294733, 19446849, 29874871, 30270055, 22390909, 15100232, 17765246, 27741487, 21382890, 23375686, 25487149, 26748104, 8882879, 11933210, 20506408, 25461735, 16627557, 27824480, 18096825, 11810272, 15890894, 23833242, 24627126, 25647241, 30586733, 27765764, 27784735, 31447099, 32977124, 32041611, 33303402, 32719484, 32522009, 32770674, 1301956, 33740630, 34037665, 27535533)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	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, Mass General Brigham Personalized Medicine	RCV000844735	SCV000712222	pathogenic	Homozygous familial hypercholesterolemia	2020-05-28	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) and has been identified in 0.004% (5/126580) of 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. 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). 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 autosomal dominant FH 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	Hypercholesterolemia, familial, 1	2016-03-01	criteria provided, single submitter	research
Invitae	RCV000587327	SCV000821038	pathogenic	Familial hypercholesterolemia	2024-01-25	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 343 of the LDLR protein (p.Gly343Ser). This variant is present in population databases (rs730882096, gnomAD 0.005%). This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 1301956, 11040093, 11933210, 15241806, 17765246, 18096825, 20506408, 22294733, 23375686, 25461735, 27765764). This variant is also known as G322S or FH-Picardie. ClinVar contains an entry for this variant (Variation ID: 183106). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt LDLR protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects LDLR function (PMID: 15100232). 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), which suggests that this may be a clinically significant amino acid residue. 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 Diagnostics, LLC DBA Color Health	RCV000587327	SCV001344025	pathogenic	Familial hypercholesterolemia	2023-01-26	criteria provided, single submitter	clinical testing	This missense variant (also known as p.Gly322Ser in the mature protein and as FH-Picardie) replaces glycine with serine at codon 343 of the LDLR protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). A functional study has shown a significantly reduced LDLR activity (15-30% of wild type) in cells from an individual compound heterozygous for this variant and another pathogenic LDLR variant p.Asp304Glu (PMID: 1301956). This variant has been shown to cause LDLR protein mis-folding and partial reduction in cell surface expression of the protein (PMID: 15100232). The mutant receptor present at the cell surface was functional with regard to its ability to bind and release LDL. This variant has been reported in over 20 individuals affected with familial hypercholesterolemia (PMID: 1301956, 11040093, 11933210, 15241806, 17765246, 18096825, 20506408, 22294733, 23375686, 25461735, 27765764, 31893465, 32770674, 34037665, 34297352). Different variants affecting the same codon (p.Gly343Asp, p.Gly343Cys, and p.Gly343Val), have been reported as disease-causing (ClinVar variation ID: 251606, 251605, 440618), suggesting that glycine at this position is important for LDLR function. This variant has been identified in 8/282454 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV000161977	SCV001433407	pathogenic	not provided	2019-08-02	criteria provided, single submitter	clinical testing
Laboratory of Molecular Genetics, National Medical Research Center for Therapy and Preventive Medicine	RCV000587327	SCV001482470	uncertain significance	Familial hypercholesterolemia		criteria provided, single submitter	research
Laboratory of molecular diagnosis of dyslipidemias, Università egli studi di Napoli Federico II	RCV000211596	SCV001653616	likely pathogenic	Hypercholesterolemia, familial, 1	2021-05-24	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000211596	SCV001737221	likely pathogenic	Hypercholesterolemia, familial, 1	2021-05-18	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000211596	SCV002022655	likely pathogenic	Hypercholesterolemia, familial, 1	2022-11-11	criteria provided, single submitter	clinical testing
AiLife Diagnostics, AiLife Diagnostics	RCV000161977	SCV002503520	pathogenic	not provided	2022-02-25	criteria provided, single submitter	clinical testing
MGZ Medical Genetics Center	RCV000211596	SCV002580607	pathogenic	Hypercholesterolemia, familial, 1	2022-03-18	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002381528	SCV002692971	pathogenic	Cardiovascular phenotype	2021-11-18	criteria provided, single submitter	clinical testing	The p.G343S pathogenic mutation (also known as c.1027G>A), located in coding exon 7 of the LDLR gene, results from a G to A substitution at nucleotide position 1027. The glycine at codon 343 is replaced by serine, an amino acid with similar properties. This alteration has been reported in a number of individuals with familial hypercholesterolemia (Hobbs HH et al. Hum Mutat. 1992;1:445-66; Reshef A et al. Hum Genet. 1996;98:581-6; Thiart R et al. Mol Cell Probes. 2000;14:299-304; Fouchier SW et al. Hum Genet. 2001;109:602-15; Nissen H et al. Clin Genet. 1998;54:79-82; Mozas P et al. Hum Mutat. 2004;24:187; Bourbon M et al. Atherosclerosis. 2008;196:633-42; Bertolini S et al. Atherosclerosis. 2013;227:342-8; Huijgen R et al. Circ Cardiovasc Genet. 2011;4:413-7; Hooper AJ et al. Atherosclerosis. 2012;224:430-4). Reduced LDLR activity was identified in some of those individuals (Hobbs HH et al. Hum Mutat. 1992;1:445-66; Thiart R et al. Mol Cell Probes. 2000;14:299-304). An in vitro study suggested that this alteration would interfere with protein folding and thus surface expression (Boswell EJ et al. J Biol Chem. 2004;279:30611-21). In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
CeGaT Center for Human Genetics Tuebingen	RCV000161977	SCV002822509	pathogenic	not provided	2024-02-01	criteria provided, single submitter	clinical testing	LDLR: PM2, PM5, PP1:Moderate, PS4:Moderate, PP4, PS3:Supporting
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV000211596	SCV004099184	pathogenic	Hypercholesterolemia, familial, 1	2023-09-28	criteria provided, single submitter	clinical testing	PS3, PS4, PM2, PM3, PP3, PP4, PP1_Strong
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	Hypercholesterolemia, familial, 1	2008-06-09	no assertion criteria provided	clinical testing
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	RCV000211596	SCV000606295	pathogenic	Hypercholesterolemia, familial, 1		no assertion criteria provided	research
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000161977	SCV001744899	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000161977	SCV001918292	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000161977	SCV001952071	likely pathogenic	not provided		no assertion criteria provided	clinical testing
Natera, Inc.	RCV000587327	SCV002086401	pathogenic	Familial hypercholesterolemia	2020-03-24	no assertion criteria provided	clinical testing
Department of Traditional Chinese Medicine, Fujian Provincial Hospital	RCV000211596	SCV002098042	pathogenic	Hypercholesterolemia, familial, 1		no assertion criteria provided	research	The missense point mutations c.G1027A (p.G343S) was identified in a family with familial hypercholesterolemia. According to the American College of Medical Genetics and Genomics (ACMG) pathogenicity rating criteria and guidelines, it was predicted that the c.G1027A mutation was pathogenic. These mutations affected LDLR binding to LDL containing APOB and APOE, resulting in the disturbance of LDL metastasis in blood and excessive siltation in tissues, leading to multiple cutaneous xanthoma and atherosclerosis.  The discovered mutations in LDLR enriched
Zotz-Klimas Genetics Lab, MVZ Zotz Klimas	RCV000211596	SCV004171582	pathogenic	Hypercholesterolemia, familial, 1	2023-11-24	no assertion criteria provided	clinical testing