19-11107433-G-T
Variant summary
Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PS4PP1_StrongPM2PP3PP4
This summary comes from the ClinGen Evidence Repository: The NM_000527.5 (LDLR):c.859G>T (p.Gly287Cys) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying evidence codes (PM2, PP3, PP4, PS4, PP1_Strong) 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: This variant is absent from gnomAD (gnomAD v2.1.1).PP3: REVEL=0.928.PP4: Variant meets PM2 and is identified in ˃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 11 unrelated index cases fulfil DLCN ≥ 6 reported in ClinGen VCI, PubMed and ClinVar: 7 cases reported in VCI, 6 of them from Service de Biochimie et de Biologie Moléculaire, Hospices Civils de Lyon, France, and 1 from Research Lab of Molecular Genetics of Lipid Metabolism-Prof. M.Arca; 3 cases reported from PubMed and at least 1 additional case reported in ClinVar from U4M-Lille University, France. From PubMed, 1 case reported In PMID 12730724 by El Messal et al, 2003, from Laboratoire de Biochimie, Faculte des Sciences Ain Chock, Casablanca, Morocco; 1 case reported in PMID 17196209 by Campagna et al, 2008, from University of Rome, Italy; 1 case reported in PMID 22669020 by El Aziz et al, 2012, from Ibn Rochd University Hospital, Casablanca, Morocco.PP1_Strong: Variant segregates with FH phenotype in 6 informative meiosis from 6 families reported from different laboratories: 4 affected relatives from 4 families tested positive for the variant, reported in VCI from Service de Biochimie et de Biologie Moléculaire, Hospices Civils de Lyon, Lyon, France; 2 affected relative is positive for the variant, reported in PMID 17196209 by Campagna et al, 2008, from University of Rome, Italy, and in PMID 22669020 by El Aziz et al, 2012, from Ibn Rochd University Hospital, Casablanca, Morocco.PS3 not met: Functional data is not available.PM5 not met: One other variant at same codon: NM_000527.5(LDLR):c.859G>A (p.Gly287Ser), ClinVar ID 161280, is classified as Uncertain significance by these guidelines, therefore PM5 is not met.PM3 not met: One case reported in VCI from Service de Biochimie et de Biologie Moléculaire, Hospices Civils de Lyon, Lyon, France. The subject is homozygous for the variant, however patient’s LDL-C is 5.32 mmol/l and no indication of lipid lowering medication. In PMID 22669020, two brothers of 21 and 18 years old are homozygous for the variant with untreated LDL-C at 12.8 mmol/l and 10.1 mmol/l respectively, which are just below 13 mmol/l threshold for HoFH phenotype. Additionally, one of 2 brothers (21 yrs with LDL-C 12.8 mmol/l) also had Type 1 diabetes. LINK:https://erepo.genome.network/evrepo/ui/classification/CA10585162/MONDO:0007750/013
Frequency
Consequence
NM_000527.5 missense
Scores
Clinical Significance
Conservation
Publications
- hypercholesterolemia, familial, 1Inheritance: AD, SD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, ClinGen
- homozygous familial hypercholesterolemiaInheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
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ACMG classification
Our verdict: Pathogenic. The variant received 12 ACMG points.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| LDLR | NM_000527.5 | c.859G>T | p.Gly287Cys | missense_variant | Exon 6 of 18 | ENST00000558518.6 | NP_000518.1 |
Ensembl
Frequencies
GnomAD3 genomes
GnomAD4 exome Cov.: 32
GnomAD4 genome
ClinVar
Submissions by phenotype
Hypercholesterolemia, familial, 1 Pathogenic:6
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The NM_000527.5 (LDLR):c.859G>T (p.Gly287Cys) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying evidence codes (PM2, PP3, PP4, PS4, PP1_Strong) 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: This variant is absent from gnomAD (gnomAD v2.1.1). PP3: REVEL=0.928. PP4: Variant meets PM2 and is identified in >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 11 unrelated index cases fulfil DLCN >= 6 reported in ClinGen VCI, PubMed and ClinVar: 7 cases reported in VCI, 6 of them from Service de Biochimie et de Biologie Moléculaire, Hospices Civils de Lyon, France, and 1 from Research Lab of Molecular Genetics of Lipid Metabolism-Prof. M.Arca; 3 cases reported from PubMed and at least 1 additional case reported in ClinVar from U4M-Lille University, France. From PubMed, 1 case reported In PMID 12730724 by El Messal et al, 2003, from Laboratoire de Biochimie, Faculte des Sciences Ain Chock, Casablanca, Morocco; 1 case reported in PMID 17196209 by Campagna et al, 2008, from University of Rome, Italy; 1 case reported in PMID 22669020 by El Aziz et al, 2012, from Ibn Rochd University Hospital, Casablanca, Morocco. PP1_Strong: Variant segregates with FH phenotype in 6 informative meiosis from 6 families reported from different laboratories: 4 affected relatives from 4 families tested positive for the variant, reported in VCI from Service de Biochimie et de Biologie Moléculaire, Hospices Civils de Lyon, Lyon, France; 2 affected relative is positive for the variant, reported in PMID 17196209 by Campagna et al, 2008, from University of Rome, Italy, and in PMID 22669020 by El Aziz et al, 2012, from Ibn Rochd University Hospital, Casablanca, Morocco. PS3 not met: Functional data is not available. PM5 not met: One other variant at same codon: NM_000527.5(LDLR):c.859G>A (p.Gly287Ser), ClinVar ID 161280, is classified as Uncertain significance by these guidelines, therefore PM5 is not met. PM3 not met: One case reported in VCI from Service de Biochimie et de Biologie Moléculaire, Hospices Civils de Lyon, Lyon, France. The subject is homozygous for the variant, however patient’s LDL-C is 5.32 mmol/l and no indication of lipid lowering medication. In PMID 22669020, two brothers of 21 and 18 years old are homozygous for the variant with untreated LDL-C at 12.8 mmol/l and 10.1 mmol/l respectively, which are just below 13 mmol/l threshold for HoFH phenotype. Additionally, one of 2 brothers (21 yrs with LDL-C 12.8 mmol/l) also had Type 1 diabetes. -
subjects mutated among 2600 FH index cases screened = 5 , family members = 5 with co-segregation (1 index case homozygote) / previously described in association with FH / Software predictions: Damaging -
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Familial hypercholesterolemia Pathogenic:3
Variant summary: LDLR c.859G>T (p.Gly287Cys) results in a non-conservative amino acid change in the encoded protein sequence. This variant is also known as p.G266C. Algorithms developed to predict the effect of missense changes on protein structure and function all suggest that this variant is likely to be disruptive. The variant was absent in 251434 control chromosomes. c.859G>T has been observed in multiple homozygous and heterozygous individuals affected with Familial Hypercholesterolemia (example: Messal_2003, El Aziz_2012, Benedek_2021). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 33955087, 12730724, 22669020). ClinVar contains an entry for this variant (Variation ID: 251489). Based on the evidence outlined above, the variant was classified as pathogenic. -
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This sequence change replaces glycine, which is neutral and non-polar, with cysteine, which is neutral and slightly polar, at codon 287 of the LDLR protein (p.Gly287Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 12730724, 17196209, 22669020, 33955087; Invitae). This variant is also known as p.G266C. ClinVar contains an entry for this variant (Variation ID: 251489). 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%. This variant disrupts the p.Gly287 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been observed in individuals with LDLR-related conditions (PMID: 23669246), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at