Submissions for variant NM_000527.5(LDLR):c.1103G>A (p.Cys368Tyr)

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
LDLR-LOVD, British Heart Foundation	RCV000237712	SCV000295220	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	RCV000237712	SCV000503297	likely pathogenic	Hypercholesterolemia, familial, 1	2016-12-16	criteria provided, single submitter	clinical testing	subjects mutated among 2600 FH index cases screened = 3 , family members = 3 with co-segregation / previously described in association with FH / Software predictions: Damaging
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille	RCV000237712	SCV000583789	pathogenic	Hypercholesterolemia, familial, 1	2017-03-30	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000781493	SCV000824206	pathogenic	Familial hypercholesterolemia	2023-11-01	criteria provided, single submitter	clinical testing	This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 368 of the LDLR protein (p.Cys368Tyr). This variant is present in population databases (rs768430352, gnomAD 0.006%). This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 1310940, 21722902, 23064986, 25461735, 26081744). This variant is also known as p.Cys347Tyr. ClinVar contains an entry for this variant (Variation ID: 251665). 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.Cys368 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9452094, 27765764). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000781493	SCV000919571	pathogenic	Familial hypercholesterolemia	2022-05-17	criteria provided, single submitter	clinical testing	Variant summary: LDLR c.1103G>A (p.Cys368Tyr) results in a non-conservative amino acid change located in the EGF-like domain (IPR000742) of 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 1.2e-05 in 251548 control chromosomes. c.1103G>A has been reported in the literature in many individuals affected with Familial Hypercholesterolemia (example Loux_1992, Mozas_2004, Robles-Osorio_2006, Ahmad_2012, Jannes_2015, Wintjens_2016, Martin-Campos_2018). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The Cys368Tyr variant was found to have reduced LDL-LDLR binding activity and LDL uptake, 40% and 60% than that of wild type, repectively (Galicia-Garcia_2020). Six clinical diagnostic laboratories and four research groups have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (4 pathogenic, 3 likely pathogenic, and 3 VUS). Based on the evidence outlined above, the variant was classified as pathogenic.
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	RCV000237712	SCV001754784	pathogenic	Hypercholesterolemia, familial, 1	2020-02-04	criteria provided, single submitter	clinical testing	The c.1103G>A variant in the LDLR gene replaces cysteine with tyrosine at codon 368 of the LDLR protein (p.Cys368Tyr). It has been reported in multiple unrelated patients with familial hypercholesterolemia (PMID: 15241806, 21722902,23064986, 25461735, 26081744) and is observed at an ultra-low frequency in the general population (gnomAD database 4/282758). This variant has been reported to be damaging by multiple bioinformatics algorithms. Other variants at the same amino acid residue have been reported as pathogenic. This variant affects a cysteine residue located within an epidermal-growth-factor (EGF) like domain of the LDLR protein. This variant was identified in a patient with familial hypercholesterolemia. Functional studies demonstrated absence of LDLR activity in fibroblasts derived from this patient. Therefore, the c.1103G>A (p.Cys368Tyr) variant in the LDLR gene is classified as pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001800607	SCV002046645	pathogenic	not provided	2021-01-13	criteria provided, single submitter	clinical testing	This variant has been reported in multiple individuals with familial hypercholesterolemia, suggesting it is likely to be associated with disease (PMID: 25461735 (2015), 24529145 (2014), 23064986 (2012), 21722902 (2011), 16314194 (2006), 15241806 (2004), 1301940 (1992)). A functional study also indicated the variant causes significant reduction in LDL binding and uptake activity (PMID: 32015373 (2020)). Based on the available information, this variant is classified as pathogenic.
AiLife Diagnostics, AiLife Diagnostics	RCV001800607	SCV002501412	likely pathogenic	not provided	2021-09-08	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002429173	SCV002744397	pathogenic	Cardiovascular phenotype	2023-12-13	criteria provided, single submitter	clinical testing	The p.C368Y pathogenic mutation (also known as c.1103G>A), located in coding exon 8 of the LDLR gene, results from a G to A substitution at nucleotide position 1103. The cysteine at codon 368 is replaced by tyrosine, an amino acid with highly dissimilar properties. Pathogenic LDLR mutations that result in the substitution or generation of cysteine residues within the cysteine-rich LDLR class A repeats and EGF-like domains are common in familial hypercholesterolemia (FH) (Villéger L. Hum Mutat. 2002;20(2):81-7). Internal structural analysis indicates this alteration eliminates a disulfide bond critical for the structural integrity of (the) EGF-like 2 domain (Ambry internal data). This variant, which is also known as p.C347Y, has been detected in several individuals with clinically diagnosed hypercholesterolemia (Loux N et al. Hum. Mutat., 1992;1:325-32; Jannes CE et al. Atherosclerosis, 2015 Jan;238:101-7; Vaca G et al. Atherosclerosis, 2011 Oct;218:391-6; Ambry internal data). Another alteration at the same codon, p.C368G (c.1102T>G), has been detected in an individual with clinically diagnosed hypercholesterolemia (Sözen MM et al. Atherosclerosis, 2005 May;180:63-71). In addition, this alteration is predicted to be deleterious by BayesDel in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Revvity Omics, Revvity	RCV000237712	SCV003827773	pathogenic	Hypercholesterolemia, familial, 1	2022-07-18	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000237712	SCV004822565	pathogenic	Hypercholesterolemia, familial, 1	2023-07-19	criteria provided, single submitter	clinical testing	This missense variant (also known as p.Cys347Tyr in the mature protein) replaces cysteine with tyrosine at codon 368 in the EGF-like repeat B of the LDLR 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). An in-vitro functional study using transfected CHO-ldlA7 cells has shown that this variant causes a reduction in LDLR binding activity and reduction in LDL uptake (PMID: 32015373). This variant has been reported in over 20 heterozygous individuals affected with familial hypercholesterolemia (PMID: 1301940, 15241806, 16314194, 21722902, 23064986, 25461735, 26081744, 30293936, 34037665). This variant has also been observed in compound heterozygous state with a known pathogenic LDLR variant in an individual affected with severe homozygous familial hypercholesterolemia, a phenotype expected of having two deleterious LDLR variants (PMID: 27784735). Different variants affecting the same codon (p.Cys368Arg, p.Cys368Ser, p.Cys368Gly), are considered to be disease-causing (ClinVar variation ID: 369848, 251666, 2109937, 251664), suggesting that cysteine at this position is important for LDLR protein function. This variant has been identified in 4/282758 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.
Laboratory of Genetics and Molecular Cardiology, University of São Paulo	RCV000237712	SCV000588554	uncertain significance	Hypercholesterolemia, familial, 1	2016-03-01	flagged submission	research
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	RCV000237712	SCV000606329	pathogenic	Hypercholesterolemia, familial, 1		no assertion criteria provided	research
Fundacion Hipercolesterolemia Familiar	RCV000237712	SCV000607559	uncertain significance	Hypercholesterolemia, familial, 1	2016-03-01	flagged submission	research
Iberoamerican FH Network	RCV000237712	SCV000748050	uncertain significance	Hypercholesterolemia, familial, 1	2016-03-01	flagged submission	research
Cohesion Phenomics	RCV000781493	SCV003836761	benign	Familial hypercholesterolemia	2023-02-09	flagged submission	clinical testing