19-11113307-C-T
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM2PP3PP4PP1_StrongPS3PS4
This summary comes from the ClinGen Evidence Repository: 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. LINK:https://erepo.genome.network/evrepo/ui/classification/CA033073/MONDO:0007750/013
Frequency
Consequence
NM_000527.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| LDLR | NM_000527.5 | c.1216C>T | p.Arg406Trp | missense_variant | Exon 9 of 18 | ENST00000558518.6 | NP_000518.1 |
Ensembl
Frequencies
GnomAD3 genomes 0.00000657 AC: 1AN: 152096Hom.: 0 Cov.: 29
GnomAD3 exomes AF: 0.0000159 AC: 4AN: 251046Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135832
GnomAD4 exome AF: 0.0000144 AC: 21AN: 1461294Hom.: 0 Cov.: 33 AF XY: 0.0000165 AC XY: 12AN XY: 726958
GnomAD4 genome 0.00000657 AC: 1AN: 152096Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0AN XY: 74298
ClinVar
Submissions by phenotype
Hypercholesterolemia, familial, 1 Pathogenic:17
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). -
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). -
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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. -
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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. -
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0/208 non-FH alleles; 0/100 healthy control individuals -
subjects mutated among 2600 FH index cases screened = 11 , family members = 7 with co-segregation / previously described in association with FH/Software predictions: Benign -
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Familial hypercholesterolemia Pathogenic:5
Variant summary: LDLR c.1216C>T (p.Arg406Trp; also known as R385W in the literature) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 251046 control chromosomes (gnomAD). c.1216C>T has been reported in the literature in multiple individuals affected with Familial Hypercholesterolemia (example: Reshef_1996, Bourbon_2008, Yang _2008, Jannes_2015, Chiou_2010). These data indicate that the variant is very likely to be associated with disease. In in vitro functional studies, the variant showed reduced low-density lipoprotein binding and uptake activity (Benito-Vicente_2015). The following publications have been ascertained in the context of this evaluation (PMID: 8882879, 17765246, 17964958, 17694954, 25461735, 25741862, 20538126). ClinVar contains an entry for this variant (Variation ID: 226351). Based on the evidence outlined above, the variant was classified as pathogenic. -
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. -
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; internal data). Invitae Evidence Modeling of clinical and family history, age, sex, and reported ancestry of multiple individuals with this LDLR variant has been performed. This variant is expected to be pathogenic with a positive predictive value of at least 99%. This is a validated machine learning model that incorporates the clinical features of 363,995 individuals referred to our laboratory for LDLR testing. This variant is also known as R385W. ClinVar contains an entry for this variant (Variation ID: 226351). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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. -
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. -
The c.1216C>T p.(Arg406Trp) missense variant in LDLR has been reported in >=10 FH patients meeting clinical criteria, including patients where secondary causes of high cholesterol have been excluded (PS4_STRONG, PP4_SUPPORTING; PMIDs 8882879, 20538126, 25741862, 32331935, 33533259, 33994402, 38122934, ClinVar, internal data). The variant has been reported to segregate with FH in >=6 affected meioses (PP1_STRONG; PMID: 25741862). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00008021 in African/African American population, which is lower than the ClinGen FH VCEP threshold (=<0.0002) for PM2_MODERATE. This variant meets level 1 pathogenic functional study criteria with <70% of wild-type activity in expression/biosynthesis, LDL binding and LDL internalization (PS3_STRONG; PMID: 25741862) and has a REVEL score of 0.883 (PP3_SUPPORTING). Based on the evidence listed above, we have classified this variant as Pathogenic. -
not provided Pathogenic:3
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. -
LDLR: PS4, PM2, PM5, PS3:Moderate -
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) -
Homozygous familial hypercholesterolemia Pathogenic:1
The p.Arg406Trp variant in LDLR has been reported in >15 individuals with hypercholesterolemia and segregated with disease in >30 affected relatives from multiple families (Reshef 1996, Bourbon 2008, Chiou 2010, Shin 2015, Jannes 2015, Medeiros 2014, Medeiros 2015, and Benito-Vicente 2015, ClinVar submission accessions: SCV000503317.1, SCV000268604.1). It has been also identified in 2/24010 African chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org/). In vitro functional studies provide some evidence that the p.Arg406Trp variant diminishes the protein activity by ~40%, suggesting that it may be a milder variant (Benito-Vicente 2015) which is consistent with the milder than expected phenotype seen in a homozygote (Medeiros 2015). Computational prediction tools and conservation analysis suggest that the p.Arg406Trp variant may impact the protein. In summary, this variant meets criteria to be classified as pathogenic for familial hypercholesterolemia in an autosomal dominant manner. The ACMG/AMP Criteria applied: PP1_Strong, PS3_Supporting, PS4, PM2_Supporting, PP3. -
LDLR-related disorder Pathogenic:1
The LDLR c.1216C>T variant is predicted to result in the amino acid substitution p.Arg406Trp. This variant (aka p.Arg385Trp) has been well-documented to be pathogenic for Familial Hypercholesterolemia (Tada et al. 2020. PubMed ID: 32331935. Table S2; Sturm et al. 2021. PubMed ID: 34037665. eTable 1; Huang et al. 2022. PubMed ID: 33994402). In ClinVar, this variant is reported as likely pathogenic or pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/226351/). This variant is reported in 0.0097% of alleles in individuals of Ashkenazi Jewish descent in gnomAD. This variant is interpreted as likely pathogenic. -
Cardiovascular phenotype Pathogenic:1
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. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at