ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.2000G>T (p.Cys667Phe)

dbSNP: rs28942083
Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 2
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
LDLR-LOVD, British Heart Foundation RCV000237926 SCV000295811 likely pathogenic Hypercholesterolemia, familial, 1 2016-03-25 criteria provided, single submitter literature only
Ambry Genetics RCV004629173 SCV005136025 likely pathogenic Cardiovascular phenotype 2024-03-26 criteria provided, single submitter clinical testing The c.2000G>T (p.C667F) alteration is located in exon 14 (coding exon 14) of the LDLR gene. This alteration results from a G to T substitution at nucleotide position 2000, causing the cysteine (C) at amino acid position 667 to be replaced by a phenylalanine (F). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant, also noted as p.C646F, has been reported in a subject with familial hypercholesterolemia (FH) (Heath, 2001). Another variant at the same codon, p.C667Y (c.2000G>A), has been described in association with FH (Leitersdorf, 1990). This amino acid position is highly conserved in available vertebrate species. Pathogenic LDLR variants 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, 2002). Internal structural analysis indicates this variant eliminates a disulfide bond critical for the structural integrity of the EGF-like 3 domain (Ambry internal data). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as likely pathogenic.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.