ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.2000G>A (p.Cys667Tyr) (rs28942083)

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Total submissions: 13
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
LDLR-LOVD, British Heart Foundation RCV000030131 SCV000295812 likely pathogenic Familial hypercholesterolemia 1 2016-03-25 criteria provided, single submitter literature only
GeneDx RCV000313287 SCV000329827 pathogenic not provided 2018-05-04 criteria provided, single submitter clinical testing The C667Y pathogenic variant in the LDLR gene (also reported as C646Y due to alternate nomenclature, and historically reported as FH French Canadian-2) has been reported multiple times in the heterozygous, compound heterozygous, and homozygous state in individuals with clinically diagnosed FH from various ethnic backgrounds (Leitersdorf et al., 1990; Cenarro et al., 1998; Foucheir et al., 2001; Mozas et al., 2004; Kublaska et al., 2008; Guardamagna et al., 2009; Chmara et al., 2010; ). The C667Y variant is considered a French Canadian founder mutation" (Leitersdorf et al., 1990; Hobbs et al., 1992; Couture et al., 1999). Furthermore, the C667Y variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). Located within the EGF-like domain 3 at a position that is conserved across species, the C667Y variant results in a non-conservative amino acid substitution which disrupts the correct formation of a disulfide bond (Jørgensen et al., 2000). Moreover, functional studies show that the C667Y variant results in abnormal LDL receptor protein folding and trafficking (Leitersdorf et al., 1990; Li et al., 2004; Sørensen et al., 2006; Oka et al., 2013)."
Robarts Research Institute,Western University RCV000030131 SCV000484740 likely pathogenic Familial hypercholesterolemia 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 RCV000030131 SCV000503450 likely pathogenic Familial hypercholesterolemia 1 2016-12-16 criteria provided, single submitter clinical testing subjects mutated among 2600 FH index cases screened = 2 , family member = 1 with co-segregation / previously described in association with FH, < 2% LDLR Activity/software prediction damaging
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille RCV000030131 SCV000583918 pathogenic Familial hypercholesterolemia 1 2017-03-30 criteria provided, single submitter clinical testing
Fundacion Hipercolesterolemia Familiar RCV000030131 SCV000607663 likely pathogenic Familial hypercholesterolemia 1 2016-03-01 criteria provided, single submitter research
Color Health, Inc RCV000775084 SCV000909188 pathogenic Familial hypercholesterolemia 2018-08-12 criteria provided, single submitter clinical testing Pathogenic variant based on current evidence: This missense variant (also known as p.Cys646Tyr in the mature protein and as FH French Canadian-2) is located in the EGF-like repeat C of the EGF precursor homology domain of the LDLR protein. Computational prediction tools and conservation analyses suggest that this variant may have deleterious impact on the protein function. Computational splicing tools suggest that this variant may not impact the RNA splicing. Experimental functional studies have shown that this variant abolishes maturation and transport of the LDLR protein to the cell surface (PMID: 2318961). While this variant is rare in the general population (1/246206 chromosomes in the Genome Aggregation Database (gnomAD)), this variant has been reported in over 30 individuals diagnosed with familial hypercholesterolemia (PMID: 2318961, 10206683, 11810272, 18263977, 25278291) and particularly common in the French Canadian population (PMID: 2318961). Based on available evidence this variant is classified as Pathogenic.
Invitae RCV000775084 SCV000930819 pathogenic Familial hypercholesterolemia 2019-05-11 criteria provided, single submitter clinical testing This sequence change replaces cysteine with tyrosine at codon 667 of the LDLR protein (p.Cys667Tyr). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and tyrosine. This variant is present in population databases (rs28942083, ExAC 0.001%). This variant has been observed in several individuals affected with familial hypercholesterolemia (PMID: 18263977, 23375686, 27765764, 2318961, 10206683, 15241806, 11810272). This variant is also known as p.Cys646Tyr in the literature. ClinVar contains an entry for this variant (Variation ID: 3689). Experimental studies have shown that this missense change results in an LDL receptor precursor protein that fails to be completely converted to the mature form. (PMID: 2318961). 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). Variants that disrupt the p.Cys667 amino acid residue in LDLR have been observed in affected individuals (PMID: 15701167, 9412789, 24507775, 11313767). This suggests that it is a clinically significant residue, and that other variants that disrupt this residue are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute RCV000030131 SCV000987457 pathogenic Familial hypercholesterolemia 1 criteria provided, single submitter clinical testing
Brunham Lab, Centre for Heart and Lung Innovation,University of British Columbia RCV000030131 SCV001432600 pathogenic Familial hypercholesterolemia 1 2019-03-03 criteria provided, single submitter research
OMIM RCV000030131 SCV000024040 pathogenic Familial hypercholesterolemia 1 1990-04-01 no assertion criteria provided literature only
Integrated Genetics/Laboratory Corporation of America RCV000030131 SCV000052786 pathogenic Familial hypercholesterolemia 1 2015-04-03 no assertion criteria provided clinical testing
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde,Academisch Medisch Centrum RCV000030131 SCV000606574 pathogenic Familial hypercholesterolemia 1 no assertion criteria provided research

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