Submissions for variant NM_000527.5(LDLR):c.859G>T (p.Gly287Cys)

dbSNP: rs375495026

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	RCV000238295	SCV004022396	pathogenic	Hypercholesterolemia, familial, 1	2023-03-24	reviewed by expert panel	curation	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.
LDLR-LOVD, British Heart Foundation	RCV000238295	SCV000295015	likely pathogenic	Hypercholesterolemia, familial, 1	2016-03-25	criteria provided, single submitter	literature only
Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix	RCV000238295	SCV000503245	pathogenic	Hypercholesterolemia, familial, 1	2016-12-16	criteria provided, single submitter	clinical testing	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
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille	RCV000238295	SCV000583750	pathogenic	Hypercholesterolemia, familial, 1	2017-03-30	criteria provided, single submitter	clinical testing
Invitae	RCV001043441	SCV001207188	likely pathogenic	Familial hypercholesterolemia	2022-05-20	criteria provided, single submitter	clinical testing	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. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 251489). This variant is also known as p.G266C. This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 12730724, 17196209, 22669020; Invitae). This variant is not present in population databases (gnomAD no frequency). 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).
Laboratory of molecular diagnosis of dyslipidemias, Università egli studi di Napoli Federico II	RCV000238295	SCV001653611	likely pathogenic	Hypercholesterolemia, familial, 1	2021-05-24	criteria provided, single submitter	clinical testing
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	RCV000238295	SCV000606252	pathogenic	Hypercholesterolemia, familial, 1		no assertion criteria provided	research
Natera, Inc.	RCV001043441	SCV002086391	likely pathogenic	Familial hypercholesterolemia	2020-08-21	no assertion criteria provided	clinical testing