Submissions for variant NM_000527.5(LDLR):c.223T>A (p.Cys75Ser)

gnomAD frequency: 0.00001  dbSNP: rs879254439

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
LDLR-LOVD, British Heart Foundation	RCV000237232	SCV000294535	likely pathogenic	Hypercholesterolemia, familial, 1	2016-03-25	criteria provided, single submitter	literature only
Invitae	RCV000775026	SCV000627031	pathogenic	Familial hypercholesterolemia	2023-10-04	criteria provided, single submitter	clinical testing	This sequence change replaces cysteine, which is neutral and slightly polar, with serine, which is neutral and polar, at codon 75 of the LDLR protein (p.Cys75Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hypercholesterolemia (PMID: 10089940; Invitae). This variant is also known as C54S. ClinVar contains an entry for this variant (Variation ID: 251079). 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. 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.Cys75 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been observed in individuals with LDLR-related conditions (PMID: 9676383, 10089940, 12124988, 17094996; Invitae), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000775026	SCV000909123	likely pathogenic	Familial hypercholesterolemia	2019-03-12	criteria provided, single submitter	clinical testing	This missense variant (also known as p.Cys54Ser in the mature protein) is located in the second LDLR type A repeat of the ligand binding domain of 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. Although functional assays have not been performed for this variant, it changes one of the functionally critical cysteine residues that form intra-repeat disulfide bonds in the ligand binding domain (PMID: 15952897) and is expected to have deleterious impact on the LDLR protein folding and stability. This variant has been identified in an individual diagnosed with familial hypercholesterolemia in U.S. (PMID: 10089940). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on available evidence, this variant is classified as Likely Pathogenic.
GeneDx	RCV001582800	SCV001810974	pathogenic	not provided	2021-02-17	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Participates in disulfide bonding with another cysteine residue which is critical for correct protein structure, and is located in the LDL-receptor class A2 repeat domain which is necessary for ligand binding (Sudhof et al., 1985; Rudenko et al., 2002); Reported as a pathogenic/likely pathogenic variant by other clinical laboratories in ClinVar (ClinVar Variant ID#251079; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 10089940)
Ambry Genetics	RCV002429164	SCV002727963	likely pathogenic	Cardiovascular phenotype	2023-10-04	criteria provided, single submitter	clinical testing	The p.C75S variant (also known as c.223T>A), located in coding exon 3 of the LDLR gene, results from a T to A substitution at nucleotide position 223. The cysteine at codon 75 is replaced by serine, an amino acid with dissimilar properties. Pathogenic LDLR mutations that result in the substitution or generation of cysteine residues within the cysteine-rich LDLR class A repeats and EGF-like domains are common in familial hypercholesterolemia (FH) (Villéger L et al. Hum Mutat. 2002;20(2):81-7). This particular cysteine alteration (also referred to as C54S) has been described in a proband with LDL-C level of 298mg/dL, in a Slovenian pediatric hypercholesterolemia cohort, and in additional probands referred for FH genetic testing (Emi M et al. Jpn Heart J. 1998;39(6):785-789; Klanar G et al. J. Am. Coll. Cardiol. 2015;66(11):1250-1257; external communication). Internal structural analysis indicates this alteration eliminates a disulfide bond critical for the structural integrity of LDLR class A repeat 2 (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000237232	SCV004848146	likely pathogenic	Hypercholesterolemia, familial, 1	2020-04-08	criteria provided, single submitter	clinical testing	proposed classification - variant undergoing re-assessment, contact laboratory