Total submissions: 23
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Clin |
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, |
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- |
RCV000211575 | SCV000295306 | likely pathogenic | Hypercholesterolemia, familial, 1 | 2016-03-25 | criteria provided, single submitter | literature only | |
Cardiovascular Research Group, |
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, |
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 - |
RCV000211575 | SCV000583806 | pathogenic | Hypercholesterolemia, familial, 1 | 2017-03-30 | criteria provided, single submitter | clinical testing | |
Laboratory of Genetics and Molecular Cardiology, |
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, |
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, |
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, |
RCV000211575 | SCV001432550 | pathogenic | Hypercholesterolemia, familial, 1 | 2018-12-07 | criteria provided, single submitter | research | |
Gene |
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, |
RCV000211575 | SCV002538606 | pathogenic | Hypercholesterolemia, familial, 1 | 2021-05-01 | criteria provided, single submitter | research | |
Ce |
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, |
RCV000211575 | SCV002809698 | pathogenic | Hypercholesterolemia, familial, 1 | 2022-03-04 | criteria provided, single submitter | clinical testing | |
Revvity Omics, |
RCV000211575 | SCV003819487 | pathogenic | Hypercholesterolemia, familial, 1 | 2023-11-01 | criteria provided, single submitter | clinical testing | |
Rady Children's Institute for Genomic Medicine, |
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, |
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, |
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, |
RCV000211575 | SCV000606362 | pathogenic | Hypercholesterolemia, familial, 1 | no assertion criteria provided | research |