Submissions for variant NM_000527.5(LDLR):c.100T>G (p.Cys34Gly)

dbSNP: rs879254405

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
LDLR-LOVD, British Heart Foundation	RCV000237876	SCV000294465	likely pathogenic	Hypercholesterolemia, familial, 1	2016-03-25	criteria provided, single submitter	literature only
Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation	RCV000237876	SCV000540717	likely pathogenic	Hypercholesterolemia, familial, 1	2016-11-05	criteria provided, single submitter	clinical testing	Disrupt disulfide bridge between Cys34 and Cys52.
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille	RCV000237876	SCV000583631	pathogenic	Hypercholesterolemia, familial, 1	2017-03-30	criteria provided, single submitter	clinical testing	ACMG Guidelines: Pathogenic (ii)
Robarts Research Institute, Western University	RCV000237876	SCV000782904	likely pathogenic	Hypercholesterolemia, familial, 1	2018-01-02	criteria provided, single submitter	clinical testing
Invitae	RCV001230907	SCV001403407	pathogenic	Familial hypercholesterolemia	2023-08-27	criteria provided, single submitter	clinical testing	This sequence change replaces cysteine, which is neutral and slightly polar, with glycine, which is neutral and non-polar, at codon 34 of the LDLR protein (p.Cys34Gly). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 20809525, 22698793, 26892515, 27824480, 30592719). ClinVar contains an entry for this variant (Variation ID: 251018). 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). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV002436069	SCV002750730	pathogenic	Cardiovascular phenotype	2018-03-15	criteria provided, single submitter	clinical testing	The p.C34G pathogenic mutation (also known as c.100T>G), located in coding exon 2 of the LDLR gene, results from a T to G substitution at nucleotide position 100. The cysteine at codon 34, located in LDLR class A repeat 1, is replaced by glycine, an amino acid with highly 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. Hum Mutat. 2002;20(2):81-7). This particular cysteine alteration has been reported in numerous FH cohorts from a variety of ethnic backgrounds with segregation reported in at least one family (Marduel M et al. Hum. Mutat., 2010 Nov;31:E1811-24; Sharifi M et al. Metab. Clin. Exp., 2016 Mar;65:48-53; Gabová D et al. Physiol Res, 2017 Mar;66:75-84). Internal structural analysis indicates this alteration eliminates a disulfide bond critical for the structural integrity of LDLR class A repeat 1 (Ambry internal data). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.