Submissions for variant NM_000527.5(LDLR):c.953G>T (p.Cys318Phe)

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
LDLR-LOVD, British Heart Foundation	RCV000237508	SCV000295111	likely pathogenic	Hypercholesterolemia, familial, 1	2016-03-25	criteria provided, single submitter	literature only
Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation	RCV000237508	SCV000540777	likely pathogenic	Hypercholesterolemia, familial, 1	2016-11-05	criteria provided, single submitter	clinical testing	Disrupt disulfide bridge between Cys318 and Cys329.
Laboratory of Genetics and Molecular Cardiology, University of São Paulo	RCV000237508	SCV000588535	likely pathogenic	Hypercholesterolemia, familial, 1	2016-03-01	criteria provided, single submitter	research
Fundacion Hipercolesterolemia Familiar	RCV000237508	SCV000607537	likely pathogenic	Hypercholesterolemia, familial, 1	2016-03-01	criteria provided, single submitter	research
Color Diagnostics, LLC DBA Color Health	RCV001176043	SCV001339860	pathogenic	Familial hypercholesterolemia	2021-04-21	criteria provided, single submitter	clinical testing	This missense variant replaces cysteine with phenylalanine at codon 318 of the LDLR protein. This variant is also known as p.Cys297Phe in the mature protein and as FH Trieste. This variant is located in the EGF-like repeat A of the EGF precursor homology domain of the LDLR protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). This variant changes one of the functionally critical cysteine residues that form intra-repeat disulfide bonds in the EGF precursor homology domain (PMID: 3495735, 4750422) and is expected to have deleterious impact on the LDLR protein folding and stability. A functional study has shown that the variant causes a significant decrease in LDLR activity (PMID: 8168830). This variant has been reported in the homozygous or compound heterozygous state (PMID: 27578128, 27784735) and in the heterozygous state (PMID: 8168830, 11317362, 15241806, 19446849, 27824480, 28161202, 31993549) in more than 20 individuals affected with familial hypercholesterolemia. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Different missense variants occurring at the same amino acid position, p.Cys318Arg and p.Cys318Tyr, are associated with disease (ClinVar variation ID: 251570, 251571), indicating that cysteine at this position is functionally and clinically important. Based on available evidence, this variant is classified as Pathogenic.
Laboratory of molecular diagnosis of dyslipidemias, Università egli studi di Napoli Federico II	RCV000237508	SCV001653613	likely pathogenic	Hypercholesterolemia, familial, 1	2021-05-24	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002379057	SCV002694610	pathogenic	Cardiovascular phenotype	2015-08-07	criteria provided, single submitter	clinical testing	The p.C318F pathogenic mutation (also known as c.953G>T and p.C297F), located in coding exon 7 of the LDLR gene, results from a G to T substitution at nucleotide position 953. The cysteine at codon 318 is replaced by phenylalanine, an amino acid with highly dissimilar properties. This mutation is located in the epidermal growth factor (EGF) precursor domain and has been observed to segregate with disease in numerous unrelated Italian familial hypercholesterolemia (FH) families (Lelli N et al. Hum. Genet. 1994;93(5):538-40, Mozas P et al. Hum. Mutat. 2004;24(2):187, Bertolini S et al. Atherosclerosis 2013;227(2):342-8). Based on the supporting evidence, p.C318F is interpreted as a disease-causing mutation.
Invitae	RCV001176043	SCV003443158	pathogenic	Familial hypercholesterolemia	2023-07-31	criteria provided, single submitter	clinical testing	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. ClinVar contains an entry for this variant (Variation ID: 251572). This variant is also known as p.Cys297Phe and/or FH Trieste. This missense change has been observed in individuals with clinical features of familial hypercholesterolemia (PMID: 8168830, 23375686, 32770674). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces cysteine, which is neutral and slightly polar, with phenylalanine, which is neutral and non-polar, at codon 318 of the LDLR protein (p.Cys318Phe). 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). For these reasons, this variant has been classified as Pathogenic.