rs730882096

chr19-11110738-G-Achr19-11110738-G-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000527.5(LDLR):c.1027G>A(p.Gly343Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000341 in 1,613,638 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G343C) has been classified as Pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000036 (0 hom.)
• Consequence: LDLR NM_000527.5 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:29 U:5 O:1
• Conservation: PhyloP100: 9.65

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 Pathogenic. Variant got 18 ACMG points.

• PM1: In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 6 uncertain in NM_000527.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr19-11110738-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 251605.Status of the report is reviewed_by_expert_panel, 3 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.995
• PP5: Variant 19-11110738-G-A is Pathogenic according to our data. Variant chr19-11110738-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 183106.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr19-11110738-G-A is described in Lovd as [Pathogenic]. Variant chr19-11110738-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LDLR	NM_000527.5	c.1027G>A	p.Gly343Ser	missense_variant	7/18	ENST00000558518.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LDLR	ENST00000558518.6	c.1027G>A	p.Gly343Ser	missense_variant	7/18	1	NM_000527.5	P3

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152144 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000656

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000279 AC: 7 AN: 251066 Hom.: 0 AF XY: 0.0000442 AC XY: 6 AN XY: 135780

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000440

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000356 AC: 52 AN: 1461494 Hom.: 0 Cov.: 31 AF XY: 0.0000440 AC XY: 32 AN XY: 727050

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000894

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000387

Gnomad4 OTH exome AF: 0.0000497

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152144 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74318

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000656

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000557 Hom.: 0

Bravo AF: 0.0000151

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ExAC AF: 0.0000247 AC: 3

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:29 Uncertain:5 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Hypercholesterolemia, familial, 1 Pathogenic:15 Uncertain:4

Pathogenic, criteria provided, single submitter	clinical testing	U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille	Mar 30, 2017	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Robarts Research Institute, Western University	-	- -
Uncertain significance, criteria provided, single submitter	research	Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge	Mar 01, 2016	0/190 non-FH alleles; 0/200 Brazilian (european ancestry) normolipidemic individuals -
Pathogenic, no assertion criteria provided	clinical testing	Zotz-Klimas Genetics Lab, MVZ Zotz Klimas	Nov 24, 2023	- -
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	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 = 7 , family members = 12 with co-segregation (1 homozygote in a family) / FH-Picardie, 15 to 30% LDLR activity / Software predictions: Damaging -
Likely pathogenic, criteria provided, single submitter	literature only	LDLR-LOVD, British Heart Foundation	Mar 25, 2016	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory of molecular diagnosis of dyslipidemias, Università egli studi di Napoli Federico II	May 24, 2021	- -
Uncertain significance, criteria provided, single submitter	research	Fundacion Hipercolesterolemia Familiar	Mar 01, 2016	- -
Pathogenic, no assertion criteria provided	research	Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Nov 11, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Sep 28, 2023	PS3, PS4, PM2, PM3, PP3, PP4, PP1_Strong -
Uncertain significance, criteria provided, single submitter	research	Iberoamerican FH Network	Mar 01, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Mar 18, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Jan 22, 2024	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. -
Pathogenic, no assertion criteria provided	clinical testing	Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital	Jun 09, 2008	- -
Pathogenic, no assertion criteria provided	research	Department of Traditional Chinese Medicine, Fujian Provincial Hospital	-	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 -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	May 18, 2021	- -
Pathogenic, reviewed by expert panel	curation	ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	Apr 28, 2023	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 M -

not provided Pathogenic:8 Other:1

Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	Feb 25, 2022	- -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	LDLR: PM2, PM5, PP1:Moderate, PS4:Moderate, PP4, PS3:Supporting -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 17, 2022	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) -
not provided, no classification provided	in vitro	Dept. of Genetics and Pharmacogenomics, Merck Research Labs	-	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	Aug 02, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Dec 11, 2018	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. -

Familial hypercholesterolemia Pathogenic:4 Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jan 26, 2023	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. -
Uncertain significance, criteria provided, single submitter	research	Laboratory of Molecular Genetics, National Medical Research Center for Therapy and Preventive Medicine	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Mar 24, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 25, 2024	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 09, 2017	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. -

Homozygous familial hypercholesterolemia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

May 28, 2020

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. -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 18, 2021

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.39
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.57
Cadd	Pathogenic	29
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.93	D;.;.;.;.;.
Eigen	Pathogenic	0.77
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	1.0	D;D;D;D;D;D
M_CAP	Pathogenic	0.91	D
MetaRNN	Pathogenic	1.0	D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.6	H;.;.;.;.;H
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Benign	0.43	T
PROVEAN	Pathogenic	-5.8	D;D;D;D;D;D
Sift	Uncertain	0.012	D;D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;D
Polyphen		1.0	D;.;.;.;.;.
Vest4		0.93
MutPred		0.98		Loss of catalytic residue at G343 (P = 0.1075);Loss of catalytic residue at G343 (P = 0.1075);.;.;.;Loss of catalytic residue at G343 (P = 0.1075);
MVP		1.0
MPC		0.46
ClinPred		0.92	D
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.78
gMVP		0.95

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs730882096; hg19: chr19-11221414;