Submissions for variant NM_000527.5(LDLR):c.781T>C (p.Cys261Arg)

dbSNP: rs1372739823

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000588356	SCV000697250	uncertain significance	not provided	2017-08-25	criteria provided, single submitter	clinical testing	Variant summary: The LDLR c.781T>C (p.Cys261Arg) variant involves the alteration of a conserved nucleotide, resulting in a missense change in one of the LDLR class A repeat domains (InterPro). 5/5 in silico tools predict a damaging outcome for this variant. This variant is absent in 121396 control chromosomes (ExAC). The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories; nor evaluated for functional impact by in vivo/vitro studies. Because of the absence of clinical information and the lack of functional studies, the variant is classified as a variant of uncertain significance (VUS) until additional information becomes available.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001216455	SCV001388252	likely pathogenic	Familial hypercholesterolemia	2023-08-01	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). 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. ClinVar contains an entry for this variant (Variation ID: 496025). This missense change has been observed in individual(s) with clinical features of familial hypercholesterolemia (Invitae). This variant is present in population databases (no rsID available, gnomAD 0.007%). This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 261 of the LDLR protein (p.Cys261Arg). This variant disrupts the p.Cys261 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9767373, 10422803, 16542394, 19062533). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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.