Total submissions: 10
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| LDLR- |
RCV000003938 | SCV000294970 | likely pathogenic | Hypercholesterolemia, familial, 1 | 2016-03-25 | criteria provided, single submitter | literature only | |
| Fundacion Hipercolesterolemia Familiar | RCV000003938 | SCV000607500 | likely pathogenic | Hypercholesterolemia, familial, 1 | 2016-03-01 | criteria provided, single submitter | research | |
| Human Genome Sequencing Center Clinical Lab, |
RCV000003938 | SCV000839987 | likely pathogenic | Hypercholesterolemia, familial, 1 | 2017-04-12 | criteria provided, single submitter | clinical testing | This c.782G>T (p.Cys261Phe) variant has previously been detected in several patients with familial hypercholesterolemia [legacy: 240 in PMID 9767373, 16542394]. The variant was also detected in a 13 y/o female, compound heterozygous for this variant and a loss of function variant [PMID 10422803]. Two siblings carried the same c.782G>T (p.Cys261Phe) heterozygous variant with only one clinically presenting hypercholesterolemia. In vitro assays showed that although the cells produced a detectable protein, cells expressing the mutant protein were unable to mediate uptake and degradation of LDL [PMID 10422803]. This variant has been reported in only one heterozygous individual from the ExAC database (http://exac.broadinstitute.org/variant/19-11217328-G-T). This variant is conserved in mammals and while not clinically validated, computer-based algorithms (SIFT and Polyphen-2) predict this p.Cys261Phe change to be deleterious. This variant is thus classified as likely pathogenic. |
| Color Diagnostics, |
RCV000776469 | SCV000912019 | likely pathogenic | Familial hypercholesterolemia | 2019-03-22 | criteria provided, single submitter | clinical testing | This missense variant (also known as p.Cys240Phe in the mature protein) is located in the sixth LDLR type A repeat of the ligand binding domain of the LDLR protein. This variant changes one of the functionally critical cysteine residues that form intra-repeat disulfide bonds in the ligand binding domain (PMID: 15952897). Computational prediction tools and conservation analyses suggest that this variant may have deleterious impact on the protein function. An experimental study has demonstrated that the variant protein shows delayed processing and accumulates as a precursor protein in the cells, resulting in defective LDL uptake and degradation (PMID: 10422803). Computational splicing tools suggest that this variant may not impact the RNA splicing. This variant has been reported in individuals with hypercholesterolemia in Sweden and Russia in compound heterozygosity with another deleterious variant in the LDLR gene (PMID: 10422803, 19062533). This variant has been identified in 10/121250 chromosomes by the Genome Aggregation Database (gnomAD). Based on available evidence, this variant is classified as Likely Pathogenic. |
| Laboratory for Molecular Medicine, |
RCV000825593 | SCV000966935 | likely pathogenic | Homozygous familial hypercholesterolemia | 2018-02-13 | criteria provided, single submitter | clinical testing | The p.Cys261Phe variant in LDLR (also described as p.Cys240Phe in the literature ), has been reported in at least 5 individuals with familial hypercholesterolemi a (FH) in the heterozygous state (Brusgaard 2006, Ekstrom 1999, Ekstrom 1998, Le ren 2004), and in 1 individual with homozygous FH who were compound heterozygote for this variant and a second pathogenic variant in LDLR, where it segregated w ith disease in 2 relatives in one family (Ekstrom 1999). This variant has also b een reported in Clinvar (Variation ID# 3740). In vitro functional studies provid e some evidence that the p.Cys261Phe variant may impact receptor uptake and degr adation (Ekstrom 1999). This variant has been identified in 2/111718 European ch romosomes by the genome Aggregation Database (gnomAD, http://gnomad.broadinstitu te.org; dbSNP rs121908040). This frequency is low enough to be consistent with t he frequency of FH in the general population. Computational prediction tools and conservation analysis suggest that the p.Cys261Phe variant may impact the prote in. In summary, although additional studies are required to fully establish its clinical significance, the p.Cys261Phe variant is likely pathogenic. ACMG/AMP Cr iteria applied (Richards 2015): PM2, PM3, PS4_Moderate, PP3, PS3_Supporting. |
| Invitae | RCV000776469 | SCV001580704 | pathogenic | Familial hypercholesterolemia | 2022-03-12 | criteria provided, single submitter | clinical testing | This variant is also known as C240F. For these reasons, this variant has been classified as Pathogenic. 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). Experimental studies have shown that this missense change affects LDLR function (PMID: 10422803). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 3740). This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 9767373, 10422803, 16542394, 19062533). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs121908040, gnomAD 0.002%). This sequence change replaces cysteine, which is neutral and slightly polar, with phenylalanine, which is neutral and non-polar, at codon 261 of the LDLR protein (p.Cys261Phe). |
| Ambry Genetics | RCV002408448 | SCV002669257 | likely pathogenic | Cardiovascular phenotype | 2018-09-21 | criteria provided, single submitter | clinical testing | The p.C261F variant (also known as c.782G>T), located in coding exon 5 of the LDLR gene, results from a G to T substitution at nucleotide position 782. The cysteine at codon 261, located in LDLR class A repeat 6, is replaced by phenylalanine, 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, also referred to as C240F, has been reported in individuals with hypercholesterolemia and in FH cohorts (Ekström U et al. Eur J Clin Invest. 1998;28:740-7; Leren TP et al. Semin Vasc Med. 2004;4:75-85; Brusgaard K et al. Clin Genet., 2006;69:277-83; Voevoda MI et al. Genetika. 2008;44(10):1374-8). This alteration was detected in compound heterozygosity with a second LDLR alteration in a proband with severe, early onset disease, and was seen alone in two affected relatives and one unaffected relative. In vitro studies indicated this variant resulted in impaired LDL uptake and degradation (Ekström U et al. Clin Genet. 1999;55:332-9). Internal structural analysis indicates this alteration eliminates a disulfide bond critical for the structural integrity of LDLR class A repeat 6 (Ambry internal data). 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. |
| New York Genome Center | RCV000003938 | SCV002764456 | pathogenic | Hypercholesterolemia, familial, 1 | 2021-11-24 | criteria provided, single submitter | clinical testing | The heterozygous c.782G>T variant identified in LDLR has previously been reported in the literature [PMIDs: 9767373, 10422803, 16542394,24507775, 31447099, 33740630] and in ClinVar [ClinVar ID: 3740] in individuals with familial hypercholesterolemia. The variant has been observed in four alleles with no homozygotes in the population databases (gnomAD v2.1.1 and v3.1.2, TOPMed Freeze 8), suggesting it is not a common variant in the populations represented in those databases. The predicted p.(Cys261Phe) variant (previously reported as p.(Cys240Phe)) resides in the exon 5 of this 18-exon gene and is located within one of the cysteine-rich LDL-receptor class A repeat domains, which contains six disulphide-bound cysteines that are critical for protein structure and stability [PMID:7603991]. In LDL receptors, the class A domains form the binding site for LDL and calcium. In vitro functional studies demonstrated delayed processing of the LDLreceptor [PMID: 10422803]. In silico prediction algorithms are in favor of damaging effect of the variant on the encoded transcript (CADD v1.6= 29.9; REVEL= 0.974). Based on available evidence this heterozygous c.782G>T p.(Cys261Phe) missense variant identified in LDLR is reported as Pathogenic. |
| OMIM | RCV000003938 | SCV000024103 | pathogenic | Hypercholesterolemia, familial, 1 | 1999-05-01 | no assertion criteria provided | literature only | |
| CSER _CC_NCGL, |
RCV002051613 | SCV000190281 | likely pathogenic | Hypercholesterolemia | 2014-06-01 | no assertion criteria provided | research |