ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.326G>A (p.Cys109Tyr) (rs121908042)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
LDLR-LOVD, British Heart Foundation RCV000211658 SCV000294631 likely pathogenic Familial hypercholesterolemia 1 2016-03-25 criteria provided, single submitter literature only
Robarts Research Institute,Western University RCV000211658 SCV000484762 likely pathogenic Familial hypercholesterolemia 1 criteria provided, single submitter clinical testing
GeneDx RCV000521830 SCV000617501 pathogenic not provided 2017-09-12 criteria provided, single submitter clinical testing The C109Y pathogenic variant (also described as C88Y due to the use of alternate nomenclature) in the LDLR gene has been reported in association with FH in individuals of varying ethnic backgrounds (Sun et al., 1998; Heath et al., 2001; Taylor et al., 2007; Tosi et al., 2007; Chmara et al., 2010; Dušková et al., 2011; Futema et al., 2012; Hooper et al., 2012; Faiz et al., 2013; Norsworthy et al., 2014; Do et al., 2015); however, segregation information is largely unavailable. Initially, C109Y was identified in a 51 year old male with a clinical diagnosis of definite FH, tendon xanthomata, and pre-treatment total cholesterol of 7.2mmol/l & LDL-C of 4.3mmol/L (Sun et al., 1998). The C109Y variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The C109Y variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This cysteine (C) residue is located in the third repeat of the ligand binding domain at a position that is conserved across species and participates in disulfide binding with the cysteine 121 residue (Rudenko et al., 2008). Furthermore, in silico analysis predicts this variant is probably damaging to the protein structure/function.
Invitae RCV000820331 SCV000961039 pathogenic Familial hypercholesterolemia 2019-08-21 criteria provided, single submitter clinical testing This sequence change replaces cysteine with tyrosine at codon 109 of the LDLR protein (p.Cys109Tyr). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and tyrosine. This variant is present in population databases (rs121908042, ExAC 0.002%). This variant has been observed in several individuals affected with familial hypercholesterolemia (PMID: 9544745, 11313767, 24956927, 22883975, 21310417, 20145306). This variant is also known as Cys88Tyr in the literature. ClinVar contains an entry for this variant (Variation ID: 226319). 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.Cys109 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been observed in individuals with LDLR-related conditions (PMID: 12009418,11313767) suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic.
Cardiovascular Genetics Laboratory,PathWest Laboratory Medicine WA - Fiona Stanley Hospital RCV000211658 SCV000268557 pathogenic Familial hypercholesterolemia 1 2008-07-22 no assertion criteria provided clinical testing
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde,Academisch Medisch Centrum RCV000211658 SCV000606087 pathogenic Familial hypercholesterolemia 1 no assertion criteria provided research

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