Total submissions: 3
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
LDLR- |
RCV000237691 | SCV000294743 | likely pathogenic | Hypercholesterolemia, familial, 1 | 2016-03-25 | criteria provided, single submitter | literature only | |
Invitae | RCV000823784 | SCV000964654 | likely pathogenic | Familial hypercholesterolemia | 2018-08-12 | criteria provided, single submitter | clinical testing | 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 is not present in population databases (ExAC no frequency). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has been observed in several individuals affected with LDLR-related conditions (PMID: 11196104, 18718593). This variant is also known in the literature as Cys146Tyr. ClinVar contains an entry for this variant (Variation ID: 251256). This sequence change replaces cysteine with tyrosine at codon 167 of the LDLR protein (p.Cys167Tyr). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and tyrosine. |
Neuberg Supratech Reference Laboratories Pvt Ltd, |
RCV000237691 | SCV004047627 | pathogenic | Hypercholesterolemia, familial, 1 | criteria provided, single submitter | clinical testing | The missense variant c.500G>A (p.Cys167Tyr) in LDLR gene has been observed in several individuals affected with LDLR-related conditions (Miyake Y et.al.,2009). 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(Bieri S et.al.,1995). In addition, missense substitutions within the LDLRA and EGF-like domains affecting cysteine residues are overrepresented among patients with hypercholesterolemia (Leigh SE et.al.,2008). This variant has been reported to the ClinVar database as Likely Pathogenic. The p.Cys167Tyr variant is novel (not in any individuals) in gnomAD Exomes and 1000 Genomes. The amino acid Cys at position 167 is changed to a Tyr changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Pathogenic. |