Submissions for variant NM_000527.5(LDLR):c.809G>A (p.Cys270Tyr)

dbSNP: rs879254683

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
LDLR-LOVD, British Heart Foundation	RCV000238081	SCV000294986	likely pathogenic	Hypercholesterolemia, familial, 1	2016-03-25	criteria provided, single submitter	literature only
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001328351	SCV001519441	pathogenic	Familial hypercholesterolemia	2022-12-12	criteria provided, single submitter	clinical testing	Variant summary: LDLR c.809G>A (p.Cys270Tyr) results in a non-conservative amino acid change located in the sixth class A repeat (IPR002172) of the encoded protein sequence. The class A repeats form the binding sites for LDL and contain six cysteine residues involved in disulfide bond formation that is required for structural integrity (InterPro). Numerous missense changes affecting cysteine residues within LDLR class A repeats are found among patients with hypercholesterolemia (HGMD), in addition, other variants affecting the same residue (i.e. Cys270), have been reported in affected individuals. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251462 control chromosomes (gnomAD). The variant, c.809G>A, (aka. c.Cys249Tyr or FH-Miami-2) has been reported in the literature in heterozygous- and compound heterozygous state in individuals affected with Familial Hypercholesterolemia (e.g. Hobbs_1992, Sun_1994, Millar_2005, Kolansky_2008, Bertolini_2013, Hsiung_2018, Yang_2021). These data indicate that the variant is very likely to be associated with disease. In one family the variant was also found in an affected family member (Yang_2021), however, in another study the variant was also reported in at least one seemingly unaffected family member (Sun_1994), which might indicate an incomplete penetrance. Publications also reported experimental evidence evaluating an impact on protein function, and demonstrated impaired LDLR activity and ligand binding in patient derived fibroblast (Hobbs_1992) and in an in-vitro expression system (Sun_1994). Another clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae	RCV001328351	SCV003443154	likely pathogenic	Familial hypercholesterolemia	2022-03-16	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 270 of the LDLR protein (p.Cys270Tyr). 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. This variant disrupts the p.Cys270 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11754108, 16250003). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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). Experimental studies have shown that this missense change affects LDLR function (PMID: 7903864). 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. ClinVar contains an entry for this variant (Variation ID: 251464). This variant is also known as C249Y or FH Miami-2. This missense change has been observed in individuals with autosomal dominant and autosomal recessive familial hypercholesterolemia (PMID: 1301956, 15637307, 23375686, 29233637, 30270083). This variant is not present in population databases (gnomAD no frequency).
Color Diagnostics, LLC DBA Color Health	RCV001328351	SCV004358495	likely pathogenic	Familial hypercholesterolemia	2023-05-08	criteria provided, single submitter	clinical testing	This missense variant (also known as p.Cys249Tyr in the mature protein) replaces cysteine with tyrosine at codon 270 in the LDLR type A repeat 6 of the LDLR protein. This variant alters a conserved cysteine residue that is critical for proper protein folding and function (PMID: 2088165, 6091915, 15952897). Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with heterozygous familial hypercholesterolemia (PMID: 1301956, 23375686, 30270083, 34220717). This variant has also been observed in compound heterozygous state with a known pathogenic LDLR variant in multiple individuals affected with severe homozygous familial hypercholesterolemia, a phenotype expected of having two deleterious LDLR variants (PMID: 7903864, 15637307; doi:10.1016/j.rccar.2019.10.006 Ruiz 2020). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	RCV000238081	SCV000606232	pathogenic	Hypercholesterolemia, familial, 1		no assertion criteria provided	research