Submissions for variant NM_000527.5(LDLR):c.1999T>C (p.Cys667Arg)

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
LDLR-LOVD, British Heart Foundation	RCV000238269	SCV000295809	likely pathogenic	Familial hypercholesterolemia 1	2016-03-25	criteria provided, single submitter	literature only
Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge	RCV000238269	SCV000322995	likely pathogenic	Familial hypercholesterolemia 1	2016-03-01	criteria provided, single submitter	research	0/200 non-FH alleles
Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies,APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix	RCV000238269	SCV000503449	likely pathogenic	Familial hypercholesterolemia 1	2016-12-16	criteria provided, single submitter	clinical testing	subject mutated among 2600 FH index cases screened = 1/software prediction damaging
Molecular Genetics Laboratory,Centre for Cardiovascular Surgery and Transplantation	RCV000238269	SCV000540851	likely pathogenic	Familial hypercholesterolemia 1	2016-11-05	criteria provided, single submitter	clinical testing	Disrupt disulfide bridge between Cys667 and Cys681.
Laboratory of Genetics and Molecular Cardiology, University of São Paulo	RCV000238269	SCV000588626	likely pathogenic	Familial hypercholesterolemia 1	2016-03-01	criteria provided, single submitter	research
Iberoamerican FH Network	RCV000238269	SCV000748170	likely pathogenic	Familial hypercholesterolemia 1	2016-03-01	criteria provided, single submitter	research
Invitae	RCV000821494	SCV000962252	pathogenic	Familial hypercholesterolemia	2019-12-20	criteria provided, single submitter	clinical testing	This sequence change replaces cysteine with arginine at codon 667 of the LDLR protein (p.Cys667Arg). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has been observed to segregate with familial hypercholesterolemia in a family (PMID: 9412789) and has been observed in individuals affected with familial hypercholesterolemia (PMID: 9412789, 23064986, 27824480, 21310417, 17765246). This variant is also known as p.Cys646Arg in the literature. ClinVar contains an entry for this variant (Variation ID: 252163). This variant disrupts the p.Cys667 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been observed in affected individuals (PMID: 15701167, 18263977, 23375686, 11313767, 9727746), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. 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.
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde,Academisch Medisch Centrum	RCV000238269	SCV000606573	pathogenic	Familial hypercholesterolemia 1		no assertion criteria provided	research