ClinVar Miner

Submissions for variant NM_000527.4(LDLR):c.782G>T (p.Cys261Phe) (rs121908040)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
LDLR-LOVD, British Heart Foundation RCV000003938 SCV000294970 likely pathogenic Familial hypercholesterolemia 1 2016-03-25 criteria provided, single submitter literature only
Fundacion Hipercolesterolemia Familiar RCV000003938 SCV000607500 likely pathogenic Familial hypercholesterolemia 1 2016-03-01 criteria provided, single submitter research
Human Genome Sequencing Center Clinical Lab,Baylor College of Medicine RCV000003938 SCV000839987 likely pathogenic Familial hypercholesterolemia 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 RCV000776469 SCV000912019 likely pathogenic Familial hypercholesterolemia 2018-08-14 criteria provided, single submitter clinical testing Likely Pathogenic variant based on current evidence: This variant (also known as p.Cys240Phe in the mature protein) is a missense variant 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, Partners HealthCare Personalized Medicine RCV000825593 SCV000966935 likely pathogenic Familial hypercholesterolemia - homozygous 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.
OMIM RCV000003938 SCV000024103 pathogenic Familial hypercholesterolemia 1 1999-05-01 no assertion criteria provided literature only
CSER _CC_NCGL, University of Washington RCV000148568 SCV000190281 likely pathogenic Hypercholesterolaemia 2014-06-01 no assertion criteria provided research

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