Submissions for variant NM_000527.5(LDLR):c.266G>A (p.Cys89Tyr)

dbSNP: rs875989894

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
LDLR-LOVD, British Heart Foundation	RCV000211649	SCV000294567	likely pathogenic	Hypercholesterolemia, familial, 1	2016-03-25	criteria provided, single submitter	literature only
Invitae	RCV000780382	SCV000627034	pathogenic	Familial hypercholesterolemia	2023-11-28	criteria provided, single submitter	clinical testing	This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 89 of the LDLR protein (p.Cys89Tyr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 9259195, 10559517, 16250003, 17142622, 19837725). This variant is also known as p.Cys68Tyr. ClinVar contains an entry for this variant (Variation ID: 226312). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt LDLR protein function with a positive predictive value of 95%. 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.Cys89 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been observed in individuals with LDLR-related conditions (PMID: 9974426, 10208479, 15241806, 20809525, 21868016), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000780382	SCV000917585	pathogenic	Familial hypercholesterolemia	2018-09-04	criteria provided, single submitter	clinical testing	Variant summary: LDLR c.266G>A (p.Cys89Tyr) results in a non-conservative amino acid change located in the second class A repeat (IPR002172) of the LDL receptor (LDLR) protein. The class A repeats form the binding sites for LDL and contain six cysteine residues involved in disulphide bond formation that is required for structural integrity (InterPro). Numerous missense changes affecting cysteine residues within the LDLR class A repeats are found among patients with hypercholesterolemia (see HGMD). Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 277232 control chromosomes (gnomAD). c.266G>A has been reported in the literature in several individuals affected with Familial Hypercholesterolemia (e.g. Graham 2005, Fouchier 2005, Humphries 2006, Tosi 2007, Wald 2016). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital	RCV000211649	SCV000268548	pathogenic	Hypercholesterolemia, familial, 1	2011-08-25	no assertion criteria provided	clinical testing