Submissions for variant NM_000527.5(LDLR):c.2041T>G (p.Cys681Gly)

dbSNP: rs879255118

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
LDLR-LOVD, British Heart Foundation	RCV000238019	SCV000295834	likely pathogenic	Hypercholesterolemia, familial, 1	2016-03-25	criteria provided, single submitter	literature only
Labcorp Genetics (formerly Invitae), Labcorp	RCV002229693	SCV000544651	pathogenic	Familial hypercholesterolemia	2023-09-26	criteria provided, single submitter	clinical testing	This variant is not present in population databases (gnomAD no frequency). This sequence change replaces cysteine, which is neutral and slightly polar, with glycine, which is neutral and non-polar, at codon 681 of the LDLR protein (p.Cys681Gly). This missense change has been observed in individuals with familial hypercholesterolemia or elevated low-density lipoprotein cholesterol (PMID: 18648394, 28964736; Invitae). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Cys681 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been observed in individuals with LDLR-related conditions (PMID: 9544745, 16092059), which suggests that this may be a clinically significant amino acid residue. 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: 252185).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000588515	SCV000697219	uncertain significance	not provided	2016-12-13	criteria provided, single submitter	clinical testing	Variant summary: The LDLR c.2041T>G (p.Cys681Gly) variant involves the alteration of a conserved nucleotide. 4/4 in silico tools predict a damaging outcome for this variant consistent with its presence in a conserved EGF precursor homology domain with is thought to be essential for positioning of the LDL-binding domain (PM1, PP5-ACMG). This variant is absent in 121120 control chromosomes (PM2-ACMG). One clinical diagnostic laboratory/reputable database classified this variant as likely pathogenic without evidence to independently evaluate. The variant of interest was reported in one patient with a severe form of treatment resistant Familial Hypercholesterolemia (FH), with characteristics of both heterozygous and homozygous FH(Snozek_2008). This patient was comprehensively evaluated to be negative for other genetic causes of FH (namely PCSK9 and ApoB). Furthermore, other variants involving the same amino acid have also been associated with FH (p.Cys681Ser, p.Cys681Tyr, p.Cys681Trp, p.Cys681Term all Likely pathogenic in ClinVar) (PM5-ACMG). Until additional clinical or functional data becomes available, this variant is classified as VUS-Possibly Pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000588515	SCV005625831	likely pathogenic	not provided	2024-02-13	criteria provided, single submitter	clinical testing	The LDLR c.2041T>G (p.Cys681Gly) variant has been reported in the published literature in individuals with familial hypercholesterolemia (FH), including one with severe symptoms (PMIDs: 28964736 (2017), 18648394 (2009)). Other missense changes at this codon (p.Cys681Ser, p.Cys681Tyr, p.Cys681Trp) have also been identified in individuals and families with FH (PMIDs: 32977124 (2020), 32331935 (2020), 7489239 (1995), 16092059 (2005)). The c.2041T>G (p.Cys681Gly) variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, this variant is classified as likely pathogenic.