ClinVar Miner

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

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Total submissions: 14
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel, ClinGen RCV000030131 SCV001960936 likely pathogenic Familial hypercholesterolemia 1 2021-06-18 reviewed by expert panel curation NM_000527.5(LDLR):c.2000G>A (p.Cys667Tyr) variant is classified as Likely pathogenic for Familial Hypercholesterolemia by applying evidence codes (PM1, PM2, PS3_Moderate, PP3, PP4 and PS4_Supporting) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines ( The supporting evidence is as follows: PM1 - Variant meets PM2 and is one of listed Cysteine. PM2 - PopMax MAF = 0.000008794 (0.0009%) in European non-Finnish exomes (gnomAD v2.1.1). PS3_moderate - PMID:2318961 - Level 2 assay - study on hmz patient's fibroblasts, after 2 hours pulse-chase, only 20% of receptors were processed to the mature form. Also here PMID: 14993243 and here PMID: 10906332 is shown that this mutant is retained on ER. In last two papers not whole LDLR cycle was studied. PP3 - REVEL: 0,986. PP4 - Variant meets PM2. Variant found in 5 unrelated index cases fulfilling validated clinical criteria for FH. PS4_supporting - Variant meets PM2. Variant identified in 5 unrelated index cases (1 case from Color laboratory with Simon-Broome criteria; 1 case from Ambry Genetics with Simon-Broome criteria; 1 case from GeneDx Inc. with Simon-Broome criteria; 2 cases from University of British Columbia with DLCN score 16 and 10, respectively).
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 2020-12-21 criteria provided, single submitter clinical testing Reported multiple times in the heterozygous, compound heterozygous, and homozygous state in individuals with clinically diagnosed FH from various ethnic backgrounds; has also been reported as C646Y due to alternate nomenclature, and historically reported as FH French Canadian-2 (see examples: 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); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); Located within the LDL-receptor EGF precursor domain and participates in disulfide bonding with another cysteine residue which is critical for correct protein structure (Sudhof et al., 1985; Rudenko et al., 2002); Published functional studies show that the C667Y variant results in abnormal LDL receptor protein folding and trafficking (Leitersdorf et al., 1990; Li et al., 2004; Srensen et al., 2006; Oka et al., 2013); This variant is associated with the following publications: (PMID: 12406975, 16257961, 17353666, 11213091, 31345425, 29407885, 32143996, 32807694, 14993243, 23375686, 11810272, 10906332, 2318961, 10206683, 1301956, 15241806, 10208489, 18263977, 19446849, 20145306, 23769672, 15556092, 28619117, 31447099, 32041611)
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 2020-09-02 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
Women's Health and Genetics/Laboratory Corporation of America, LabCorp 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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