ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.1216C>T (p.Arg406Trp)

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Total submissions: 23
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel RCV000211575 SCV002506381 pathogenic Hypercholesterolemia, familial, 1 2022-04-22 reviewed by expert panel curation The NM_000527.5(LDLR):c1216C>T (p.Arg406Trp) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying evidence codes PM2, PP3, PS3, PS4, PP1_Strong, and PP4 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: PM2 - PopMax MAF = 0.000097 (0.0097%) in Ashkenazi Jewish exomes+genomes (gnomAD v2.1.1). PP3 - REVEL = 0.88, which is above the threshold of 0.75. PS3 – Level 1 functional studies: PMID: 2574186; Heterologous cells (CHO), FACS assays - variant results in 60-65% LDLR expression/biosynthesis, LDL binding and LDL internalization compared to wild-type; results meet <70% threshold. PS4 – Variant meets PM2 and is identified in at least 19 unrelated index cases who fulfill clinical criteria for FH (1 case with DLCN criteria from PathWest Laboratory Medicine WA – FH VCEP member lab; 18 cases with SB criteria from Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge – FH VCEP member lab). PP1_Strong – Variant segregates with phenotype in 31 informative meioses from 15 families in data provided by FH VCEP member labs (Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge – 11 families: 23 affected with the variant and 1 unaffected without the variant; Laboratory of Genetics and Molecular Cardiology – 4 families: 4 affected with the variant and 3 unaffected without the variant). PP4 - Variant meets PM2. Identified in >1 case who met clinical criteria for FH after alternative causes for high cholesterol were excluded. Note: two other missense variants at this same codon have been reported: 1) NM_000527.5(LDLR):c.1217G>A (p.Arg406Gln) – Likely pathogenic by these guidelines. 2) NM_000527.5(LDLR):c.1217G>C (p.Arg406Pro) – Likely pathogenic by these guidelines. -PM5 not applicable as such variants must be Pathogenic.
Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital RCV000211575 SCV000268604 pathogenic Hypercholesterolemia, familial, 1 2022-04-05 criteria provided, single submitter clinical testing The LDLR p.Arg406Trp variant has been described in multiple cohorts of familial hypercholesterolemia patients and their families, and in vitro studies have showed a 40% reduction in LDL-receptor activity compared to wild-type LDL-receptor (PMID: 25741862).
LDLR-LOVD, British Heart Foundation RCV000211575 SCV000295306 likely pathogenic Hypercholesterolemia, familial, 1 2016-03-25 criteria provided, single submitter literature only
Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge RCV000211575 SCV000322937 likely pathogenic Hypercholesterolemia, familial, 1 2016-03-01 criteria provided, single submitter research 0/208 non-FH alleles; 0/100 healthy control individuals
Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix RCV000211575 SCV000503317 likely pathogenic Hypercholesterolemia, familial, 1 2016-12-16 criteria provided, single submitter clinical testing subjects mutated among 2600 FH index cases screened = 11 , family members = 7 with co-segregation / previously described in association with FH/Software predictions: Benign
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille RCV000211575 SCV000583806 pathogenic Hypercholesterolemia, familial, 1 2017-03-30 criteria provided, single submitter clinical testing
Laboratory of Genetics and Molecular Cardiology, University of São Paulo RCV000211575 SCV000588566 likely pathogenic Hypercholesterolemia, familial, 1 2016-03-01 criteria provided, single submitter research
Fundacion Hipercolesterolemia Familiar RCV000211575 SCV000607575 likely pathogenic Hypercholesterolemia, familial, 1 2016-03-01 criteria provided, single submitter research
Iberoamerican FH Network RCV000211575 SCV000748143 likely pathogenic Hypercholesterolemia, familial, 1 2016-03-01 criteria provided, single submitter research
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute RCV000211575 SCV000987565 pathogenic Hypercholesterolemia, familial, 1 criteria provided, single submitter clinical testing
Invitae RCV001045722 SCV001209593 pathogenic Familial hypercholesterolemia 2024-01-09 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 406 of the LDLR protein (p.Arg406Trp). This variant is present in population databases (rs121908043, gnomAD 0.01%). This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 8882879, 20538126, 25461735, 25741862, 26343872; Invitae). This variant is also known as R385W. ClinVar contains an entry for this variant (Variation ID: 226351). 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: 25741862). This variant disrupts the p.Arg406 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been observed in individuals with LDLR-related conditions (PMID: 16250003), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Broad Institute Rare Disease Group, Broad Institute RCV000211575 SCV001422933 pathogenic Hypercholesterolemia, familial, 1 2020-01-22 criteria provided, single submitter curation The p.Arg406Trp variant in LDLR has been reported in at least 51 individuals (including 48 Portuguese, 1 Taiwanese, 1 Korean, and 1 Ashkenazi Jewish individuals) with Familial Hypercholesterolemia, segregated with disease in 48 affected relatives from 18 families (PMID: 17765246, 20538126, 26343872, 8882879, 25741862), and has been identified in 0.009658% (1/10354) of Ashkenazi Jewish chromosomes and 0.008021% (2/24936) of African chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs121908043). Please note that for diseases with clinical variability, or reduced penetrance, pathogenic variants may be present at a low frequency in the general population. This variant has also been reported likely pathogenic and pathogenic in ClinVar (Variation ID: 226351). In vitro functional studies provide some evidence that the p.Arg406Trp variant may impact cell surface expression and receptor activity (PMID: 25741862). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, this variant meets criteria to be classified as pathogenic for Familial Hypercholesterolemia in an autosomal dominant manner based on cosegregation with disease and multiple reports in individuals with Familial Hypercholesterolemia. ACMG/AMP Criteria applied: PP1_Strong, PS4, PS3_supporting, PP3 (Richards 2015).
Brunham Lab, Centre for Heart and Lung Innovation, University of British Columbia RCV000211575 SCV001432550 pathogenic Hypercholesterolemia, familial, 1 2018-12-07 criteria provided, single submitter research
GeneDx RCV001560136 SCV001782484 pathogenic not provided 2023-08-08 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies demonstrate that p.(R406W) results in decreased LDLR expression as well as reduced LDL binding and uptake, and is described as a mild pathogenic variant (Benito-Vicente et al., 2015); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as p.(R385W); This variant is associated with the following publications: (PMID: 8882879, 17765246, 19318025, 20538126, 31589614, 33069457, 30586733, 30876530, 33087929, 31491741, 32719484, 32331935, 33740630, 34037665, 26343872, 34456049, 33994402, 25741862)
Laan Lab, Human Genetics Research Group, University of Tartu RCV000211575 SCV002538606 pathogenic Hypercholesterolemia, familial, 1 2021-05-01 criteria provided, single submitter research
CeGaT Center for Human Genetics Tuebingen RCV001560136 SCV002546064 pathogenic not provided 2022-04-01 criteria provided, single submitter clinical testing LDLR: PS4, PM2, PM5, PS3:Moderate
Ambry Genetics RCV002354591 SCV002655472 pathogenic Cardiovascular phenotype 2022-10-31 criteria provided, single submitter clinical testing The p.R406W pathogenic mutation (also known as c.1216C>T), located in coding exon 9 of the LDLR gene, results from a C to T substitution at nucleotide position 1216. The arginine at codon 406 is replaced by tryptophan, an amino acid with dissimilar properties. This alteration has been detected in individuals with hypercholesterolemia and reported to co-segregate with disease in multiple cases (Reshef A et al. Hum. Genet., 1996 Nov;98:581-6; Benito-Vicente A et al. Genet. Med., 2015 Dec;17:980-8; Jannes CE et al. Atherosclerosis. 2015 Jan;238(1):101-7; Shin DG et al. Atherosclerosis. 2015 Nov;243(1):53-8; Chiou KR et al. J Clin Lipidol 2017 Jan;11:386-393.e6; Tada H et al. J Clin Lipidol. Mar;14(3):346-351.e9). In limited functional studies, this alteration was reported to demonstrate approximately 60% of normal LDLR activity (Benito-Vicente A et al. Genet. Med., 2015 Dec;17:980-8). This variant has been detected in the homozygous state in a case with hypercholesterolemia, but not typical homozygous familial hypercholesterolemia phenotype, suggesting it may have a more mild impact (Medeiros AM et al. Genet Med. 2016 Apr;18(4):316-24). Alternate amino acid substitutions at this position, R406P and R406Q, have also be reported in hypercholesterolemia cohorts (Thiart R et al. J Med Genet. 2000 Jul;37(7):514-9; Fouchier SW et al. Hum. Mutat., 2005 Dec;26:550-6). 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.
Fulgent Genetics, Fulgent Genetics RCV000211575 SCV002809698 pathogenic Hypercholesterolemia, familial, 1 2022-03-04 criteria provided, single submitter clinical testing
Revvity Omics, Revvity Omics RCV000211575 SCV003819487 pathogenic Hypercholesterolemia, familial, 1 2023-11-01 criteria provided, single submitter clinical testing
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego RCV001045722 SCV004046052 pathogenic Familial hypercholesterolemia criteria provided, single submitter clinical testing This variant is also referred to as c.1216C>T (p.Arg385Trp) in the literature. This variant has been previously reported as a heterozygous and homozygous change in patients with familial hypercholesterolemia (PMID: 8882879, 25741862, 30876530, 31491741, 32331935). Functional studies demonstrate that p.Arg406Trp results in decreased LDLR expression and reduced LDL binding and uptake (PMID: 25741862). The c.1216C>T (p.Arg406Trp) variant is present in the heterozygous state in the gnomAD population database at a frequency of 0.001% (5/282390) and thus is presumed to be rare. The c.1216C>T (p.Arg406Trp) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Based on the available evidence, the c.1216C>T (p.Arg406Trp) variant is classified as Pathogenic.
Color Diagnostics, LLC DBA Color Health RCV001045722 SCV004358514 pathogenic Familial hypercholesterolemia 2023-08-02 criteria provided, single submitter clinical testing This missense variant replaces arginine with tryptophan at codon 406 of the LDLR protein. It is also known as p.Arg385Trp in the mature protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown that this variant causes partial reduction of LDLR activity by about 40% compared to wild-type (PMID: 25741862). This LDLR variant has been reported in individuals affected with autosomal dominant familial hypercholesterolemia (PMID: 8882879, 17694954, 17765246, 20538126, 25461735, 26020417, 26343872, 28502495, 30876530, 32331935, 33533259, 33994402). This variant has also been observed in both homozygous and compound heterozygous state with a known pathogenic LDLR variant in individuals affected with severe homozygous familial hypercholesterolemia, a phenotype expected of having two deleterious LDLR variants (PMID: 20538126, 26020417). This variant has been identified in 5/282390 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Different missense variants occurring at the same codon, p.Arg406Gln and p.Arg406Pro, are known to cause disease (ClinVar Variation ID: 228798, 226352), indicating that arginine at this position may be important for LDLR protein function. Based on the available evidence, this variant is classified as Pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV001560136 SCV004563519 pathogenic not provided 2023-10-31 criteria provided, single submitter clinical testing The LDLR c.1216C>T; p.Arg406Trp variant (rs121908043) is reported in the literature in numerous individuals affected with familial hypercholesterolemia (Benito-Vicente 2015, Bourbon 2008, Chiou 2010, Huang 2022, Medeiros 2016, Tada 2020). This variant is also reported as pathogenic by an expert panel in ClinVar (Variation ID: 226351). This variant is found in the general population with an overall allele frequency of 0.002% (5/282,390 alleles) in the Genome Aggregation Database. In vitro functional analyses demonstrate the variant protein has significantly reduced LDLR activity, binding and uptake (Benito-Vicente 2015). Computational analyses predict that this variant is deleterious (REVEL: 0.883). Based on available information, this variant is considered to be pathogenic. References: Benito-Vicente A et al.The importance of an integrated analysis of clinical, molecular, and functional data for the genetic diagnosis of familial hypercholesterolemia. Genet Med. 2015 Dec;17(12):980-8. PMID: 25741862. Bourbon M et al. Familial hypercholesterolaemia in Portugal. Atherosclerosis. 2008 Feb;196(2):633-42. PMID: 17765246. Chiou KR et al. Detection of mutations and large rearrangements of the low-density lipoprotein receptor gene in Taiwanese patients with familial hypercholesterolemia. Am J Cardiol. 2010 Jun 15;105(12):1752-8. PMID: 20538126. Huang CC et al. Genetic Analysis in a Taiwanese Cohort of 750 Index Patients with Clinically Diagnosed Familial Hypercholesterolemia. J Atheroscler Thromb. 2022 May 1;29(5):639-653. PMID: 33994402. Medeiros AM et al. Mutational analysis of a cohort with clinical diagnosis of familial hypercholesterolemia: considerations for genetic diagnosis improvement. Genet Med. 2016 Apr;18(4):316-24. PMID: 26020417. Tada H et al. A catalog of the pathogenic mutations of LDL receptor gene in Japanese familial hypercholesterolemia. J Clin Lipidol. 2020 May-Jun;14(3):346-351.e9. PMID: 32331935.
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum RCV000211575 SCV000606362 pathogenic Hypercholesterolemia, familial, 1 no assertion criteria provided research

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