Submissions for variant NM_000527.5(LDLR):c.664T>C (p.Cys222Arg)

gnomAD frequency: 0.00001  dbSNP: rs577934998

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	RCV000211577	SCV004022457	likely pathogenic	Hypercholesterolemia, familial, 1	2023-04-28	reviewed by expert panel	curation	The NM_000527.5(LDLR):c.664T>C (p.Cys222Arg) variant is classified as a Likely pathogenic variant for Familial Hypercholesterolemia by applying evidence codes PM2, PM1, PM3, PS4_supporting, PP3, 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 = 0.0001098 (0.01%) in East Asian exomes (gnomAD v2.1.1) PM1: Variant meets PM2 and alters Cys222, one of the cysteine residues listed. PM3: Variant meets PM2 and is identified in two index cases with homozygous FH phenotype (LDL mmol/L = 17.9 and 14.09 respectively), PMID: 15823276 PS4_supporting: Variant meets PM2 and is identified in at least 5 index cases who fulfill SB possible/definite FH or DLCN>=6 criteria for FH from GeneDx Inc., Ambry Genetics, and the Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA) PP3 : REVEL = 0.966. PP4: Variant meets PM2 and identified in at least 2 FH case from GeneDx Inc, 1 FH case from Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA), and 1 FH case from Ambry Genetics, all of them fulfilling SB criteria for possible/definite FH or DLCN > 6.
LDLR-LOVD, British Heart Foundation	RCV000211577	SCV000294868	likely pathogenic	Hypercholesterolemia, familial, 1	2016-03-25	criteria provided, single submitter	literature only
Robarts Research Institute, Western University	RCV000211577	SCV000484706	likely pathogenic	Hypercholesterolemia, familial, 1		criteria provided, single submitter	clinical testing
Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix	RCV000211577	SCV000503200	uncertain significance	Hypercholesterolemia, familial, 1	2016-12-16	criteria provided, single submitter	clinical testing	subject mutated among 2600 FH index cases screened = 1 , family member = 1 /FH-France / Software predictions: Damaging
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille	RCV000211577	SCV000583716	pathogenic	Hypercholesterolemia, familial, 1	2017-03-30	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000799446	SCV000939108	pathogenic	Familial hypercholesterolemia	2024-01-04	criteria provided, single submitter	clinical testing	This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 222 of the LDLR protein (p.Cys222Arg). This variant is present in population databases (rs577934998, gnomAD 0.01%). This missense change has been observed in individuals with hypercholesterolemia (PMID: 15823276, 22883975, 25043216; Invitae). This variant is also known as C201R and c.541T>C. ClinVar contains an entry for this variant (Variation ID: 226332). 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 affects a cysteine residue located within an LDLRA or epidermal-growth-factor (EGF)-like domains of the LDLR protein. Cysteine residues in these domains have been shown to be involved in the formation of disulfide bridges, which are critical for protein structure and stability (PMID: 7548065, 7603991, 7979249). In addition, missense substitutions within the LDLRA and EGF-like domains affecting cysteine residues are overrepresented among patients with hypercholesterolemia (PMID: 18325082). This variant disrupts the p.Cys222 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been observed in individuals with LDLR-related conditions (PMID: 7573037, 24671153), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000985769	SCV001134267	likely pathogenic	not provided	2018-10-16	criteria provided, single submitter	clinical testing	The best available variant frequency is uninformative because it is below the disease allele frequency. Statistically enriched in patients compared to ethnically matched controls. Predicted to have a damaging effect on the protein.
Brunham Lab, Centre for Heart and Lung Innovation, University of British Columbia	RCV000211577	SCV001432568	likely pathogenic	Hypercholesterolemia, familial, 1	2019-03-13	criteria provided, single submitter	research
GeneDx	RCV000985769	SCV001753429	pathogenic	not provided	2024-06-20	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as p.(C201R), c.541 T>C; This variant is associated with the following publications: (PMID: 12553167, 15823288, 22883975, 25043216, 34426522, 32041611, 33740630, 34037665, 2988123, 12459547, 15823276, 33994402, 36685950, 38138952)
Revvity Omics, Revvity	RCV000211577	SCV002022664	likely pathogenic	Hypercholesterolemia, familial, 1	2022-08-30	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000799446	SCV002572225	pathogenic	Familial hypercholesterolemia	2022-08-22	criteria provided, single submitter	clinical testing	Variant summary: LDLR c.664T>C (p.Cys222Arg) 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 8e-06 in 249776 control chromosomes (gnomAD). c.664T>C has been reported in the literature in multiple individuals affected with Familial Hypercholesterolemia (examples: Hooper_2012, Martn-Campos_2018, and Leren_2021). These data indicate that the variant is very likely to be associated with disease. Other variants located at the same codon have been reported in association with Hypercholesterolaemia (C222G, C222F, C222W, C222Y; HGMD). Eight submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic/likely pathogenic (n=7) and VUS (n=1). Based on the evidence outlined above, the variant was classified as pathogenic.
Ambry Genetics	RCV002363058	SCV002663260	likely pathogenic	Cardiovascular phenotype	2019-03-26	criteria provided, single submitter	clinical testing	The p.C222R variant (also known as c.664T>C), located in coding exon 4 of the LDLR gene, results from a T to C substitution at nucleotide position 664. The cysteine at codon 222 is replaced by arginine, an amino acid with highly dissimilar properties. This alteration, also referred to as p.C201R, has been reported in multiple patients with familial hypercholesterolemia (Damgaard D et al. Atherosclerosis. 2005;180:155-60; Sözen MM et al. Atherosclerosis. 2005;180:63-71; Hooper AJ et al. Atherosclerosis. 2012;224:430-4; Zhao X et al. Int J Cardiol. 2014;176:e15-9). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Furthermore, internal structural analysis predicts this alteration to disrupt a cysteine-cysteine bridge in a conserved motif in a region of known function (Fass D et al. Nature. 1997;388(6643):691-3). Alterations at the same amino acid position, p.C222G (Taylor A et al. Clin Genet. 2010;77:572-80), C222F (Fouchier SW et al. Hum Genet. 2001;109:602-15), p.C222W (Medeiros AM et al. Genet Med. 2016;18:316-24) and p.C222Y (Koivisto UM et al. Am J Hum Genet. 1995;57:789-97), have also been reported in individuals with hypercholesterolemia. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Genesolutions, Medical Genetics Institutes, Ho Chi Minh City, Vietnam	RCV000211577	SCV002820068	pathogenic	Hypercholesterolemia, familial, 1	2023-01-16	criteria provided, single submitter	clinical testing	The patient was admitted to the Interventional Cardiology department, Nhan Dan Gia Dinh hospital, Vietnam and was diagnosed with stable angina CCS III (confirmed by Coronary MSCT), Triple vessel disease, and Hypertension. Furthermore, she had hyperlipidemia with a sign of Arcus Senilis in both eyes. Before that, her older sister was also diagnosed with hyperlipidemia. Her genetic testing showed a heterogeneous variant of LDLR gene, c.664T>C (p.Cys222Arg). This variant affects the p.Cys222 amino acid residue in LDLR. Despite its “Conflicting interpretations of pathogenicity” in ClinVar (only 4 over 10 submissions recorded with pathogenic status), her clinical features strongly suggest the diagnosis of Familial Hypercholesterolemia. This mutation record is expected to contribute to the clinical significance of the variant. The Interventional Cardiology department, Nhan Dan Gia Dinh hospital, Ho Chi Minh City, Vietnam played a main role in diagnosing this case.
All of Us Research Program, National Institutes of Health	RCV000211577	SCV004836929	likely pathogenic	Hypercholesterolemia, familial, 1	2023-10-02	criteria provided, single submitter	clinical testing	This missense variant replaces cysteine with arginine at codon 222 in the LDLR type A repeat 5 of the LDLR protein. This variant is also known as p.Cys201Arg in the mature protein. This variant alters a conserved cysteine residue that is critical for proper protein folding and function (PMID: 2088165, 6091915, 15952897). 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in over 10 individuals affected with familial hypercholesterolemia (PMID: 10532689, 15823276, 15823288, 22883975, 25043216, 30293936, 31345425, 32829317, 33740630, 33994402). This variant has been identified in 2/249776 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Multiple different variants affecting the same codon are considered to be disease-causing (ClinVar variation ID: 183093, 251362, 251365, 251361), suggesting that cysteine at this position is important for LDLR protein function. Based on the available evidence, this variant is classified as Likely Pathogenic.
Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital	RCV000211577	SCV000268578	pathogenic	Hypercholesterolemia, familial, 1	2008-06-05	no assertion criteria provided	clinical testing
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	RCV000211577	SCV000606188	pathogenic	Hypercholesterolemia, familial, 1		no assertion criteria provided	research