Submissions for variant NM_000527.5(LDLR):c.1102T>C (p.Cys368Arg)

dbSNP: rs879254791

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Robarts Research Institute, Western University	RCV000408876	SCV000484748	likely pathogenic	Hypercholesterolemia, familial, 1		criteria provided, single submitter	clinical testing
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille	RCV000408876	SCV000583788	pathogenic	Hypercholesterolemia, familial, 1	2017-03-30	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV002230212	SCV000818723	pathogenic	Familial hypercholesterolemia	2023-12-20	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 368 of the LDLR protein (p.Cys368Arg). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 9452094, 27765764). It has also been observed to segregate with disease in related individuals. This variant is also known as p.Cys347Arg. ClinVar contains an entry for this variant (Variation ID: 369848). 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 observed in individuals with LDLR-related conditions (PMID: 1310940, 9452094, 15823276, 21722902, 23064986, 25461735, 26081744, 27765764), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV000408876	SCV000987459	pathogenic	Hypercholesterolemia, familial, 1		criteria provided, single submitter	clinical testing
Brunham Lab, Centre for Heart and Lung Innovation, University of British Columbia	RCV000408876	SCV001432591	pathogenic	Hypercholesterolemia, familial, 1	2019-05-10	criteria provided, single submitter	research
GeneDx	RCV002275000	SCV002562549	likely pathogenic	not provided	2024-01-31	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; This variant is associated with the following publications: (PMID: 32041611, 34037665, 27765764, 9452094)
Ambry Genetics	RCV002429335	SCV002742917	pathogenic	Cardiovascular phenotype	2024-05-22	criteria provided, single submitter	clinical testing	The p.C368R pathogenic mutation (also known as c.1102T>C), located in coding exon 8 of the LDLR gene, results from a T to C substitution at nucleotide position 1102. The cysteine at codon 368 is replaced by arginine, 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 (also referred to as p.C347R) has been reported in probands with FH, and has been reported to segregate with disease in families (Couture P et al. Hum Mutat, 1998;Suppl 1:S226-31; Drouin-Chartier JP et al. Metabolism, 2015 Nov;64:1541-7; Wang J et al. Arterioscler Thromb Vasc Biol, 2016 12;36:2439-2445; Garg A et al. J Endocr Soc, 2020 Jan;4:bvz015). Two other variants at the same codon, p.C368Y (legacy p.C347Y, c.1103G>A) and p.C368G (legacy p.C347G, c.1102T>G), have also been detected in individuals with hypercholesterolemia (Loux N et al. Hum. Mutat., 1992;1:325-32; Sözen MM et al. Atherosclerosis, 2005 May;180:63-71). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	RCV000408876	SCV000606327	pathogenic	Hypercholesterolemia, familial, 1		no assertion criteria provided	research