Submissions for variant NM_000527.5(LDLR):c.463T>G (p.Cys155Gly)

dbSNP: rs879254535

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
LDLR-LOVD, British Heart Foundation	RCV000237671	SCV000294726	likely pathogenic	Hypercholesterolemia, familial, 1	2016-03-25	criteria provided, single submitter	literature only
Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix	RCV000237671	SCV000503163	likely pathogenic	Hypercholesterolemia, familial, 1	2016-12-16	criteria provided, single submitter	clinical testing	subjects mutated among 2600 FH index cases screened = 6 , family members = 6 with co-segregation / FH-Germany / Software predictions: Damaging
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille	RCV000237671	SCV000583683	pathogenic	Hypercholesterolemia, familial, 1	2017-03-30	criteria provided, single submitter	clinical testing
Robarts Research Institute, Western University	RCV000237671	SCV000782948	likely pathogenic	Hypercholesterolemia, familial, 1	2018-01-02	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000712214	SCV000842652	likely pathogenic	not provided	2017-11-22	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000712214	SCV002063725	likely pathogenic	not provided	2021-12-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000712214	SCV002073982	pathogenic	not provided	2022-01-25	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Participates in disulfide bonding with another cysteine residue which is critical for correct protein structure, and is located in the LDL-receptor class A4 repeat domain which is necessary for ligand binding (Sudhof et al., 1985; Rudenko et al., 2002); Different missense changes at this residue, p.(C155R), p.(C155F), p.(C155Y), have been reported in the Human Gene Mutation Database in association with FH (HGMD); Also known as p.(C134G) and FH Germany; Reported in ClinVar but additional evidence is not available (ClinVar Variant ID#251239; ClinVar); This variant is associated with the following publications: (PMID: 32041611, 33740630, 1301956, 10735632, 10090473, 9104431, 14974088, 26894473)
Labcorp Genetics (formerly Invitae), Labcorp	RCV001854887	SCV002229830	pathogenic	Familial hypercholesterolemia	2024-05-22	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 155 of the LDLR protein (p.Cys155Gly). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 9104431, 10735632, 14974088). This variant is also known as C134G and FH Germany. ClinVar contains an entry for this variant (Variation ID: 251239). 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 with a positive predictive value of 95%. 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.Cys155 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been observed in individuals with LDLR-related conditions (PMID: 9104431, 10735632, 14974088, 20809525, 21382890), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
MGZ Medical Genetics Center	RCV000237671	SCV002580937	pathogenic	Hypercholesterolemia, familial, 1	2022-07-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002327175	SCV002633610	pathogenic	Cardiovascular phenotype	2022-08-19	criteria provided, single submitter	clinical testing	The p.C155G pathogenic mutation (also known as c.463T>G), located in coding exon 4 of the LDLR gene, results from a T to G substitution at nucleotide position 463. The cysteine at codon 155, located at LDLR class A repeat 4, 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 variant (also known as p.C134G and FH Germany) has been reported in multiple FH cohorts in heterozygous and compound heterozygote cases (Hobbs HH et al. Hum. Mutat. 1992;1:445-66; Lombardi MP et al. Clin. Genet. 2000 Feb;57:116-24; Dedoussis GV et al. Hum. Mutat. 2004 Mar;23:285-6; Koeijvoets KC et al. Atherosclerosis. 2005 May;180:93-9; Sanna C et al. Atherosclerosis. 2016 Apr;247:97-104). Alternate amino acid substitutions at this position, including p.C155R and p.C155F, have also been reported in individuals with FH (Yu W et al. Atherosclerosis. 2002 Dec;165:335-42; van der Graaf A et al. Circulation. 2011 Mar;123:1167-73). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Genetics and Molecular Pathology, SA Pathology	RCV000237671	SCV004175299	likely pathogenic	Hypercholesterolemia, familial, 1	2022-12-16	criteria provided, single submitter	clinical testing	The LDLR c.463T>G variant is classified as LIKELY PATHOGENIC (PS4_Moderate, PM1, PM2, PP3, PP4) The LDLR c.463T>G variant is a single nucleotide change in exon 4 of 18 of the LDLR gene, which is predicted to change the amino acid cysteine at position 155 in the protein to glycine. This variant has been reported in a number of individuals affected with familial hypercholesterolemia (PMID: 33955087, 10735632, 14974088, 9104431, 33740630) (PS4_Mod). Note this variant has also been described as Cys134Gly or FH Germany in the literature. The cysteine residue is highly conserved across species and is located in a region that is involved in disulphide bond formation, which is critical for protein structure, stability and binding (PMID: 7603991) (PM1). This variant is absent from population databases (PM2) and has been reported as Pathogenic/Likely pathogenic by other diagnostic laboratories (ClinVar Variation ID: 251239). This variant is also reported in dbSNP (rs879254535), LOVD (LDLR_001739) and HGMD (CM920414). Computational predictions support a deleterious effect on the gene or gene product (PP3). The clinical features of this case are highly specific for a variant in the LDLR gene and this patient has a well-defined syndrome with little overlap with other clinical presentations (PP4).
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	RCV000237671	SCV000606127	pathogenic	Hypercholesterolemia, familial, 1		no assertion criteria provided	research