ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.1721G>A (p.Arg574His)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
LDLR-LOVD, British Heart Foundation RCV000237135 SCV000295612 likely pathogenic Familial hypercholesterolemia 1 2016-03-25 criteria provided, single submitter literature only
Laboratory of Genetics and Molecular Cardiology, University of São Paulo RCV000237135 SCV000588604 uncertain significance Familial hypercholesterolemia 1 2016-03-01 criteria provided, single submitter research
Fundacion Hipercolesterolemia Familiar RCV000237135 SCV000607631 uncertain significance Familial hypercholesterolemia 1 2016-03-01 criteria provided, single submitter research
Invitae RCV000791382 SCV000836468 likely pathogenic Familial hypercholesterolemia 2019-11-11 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 574 of the LDLR protein (p.Arg574His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs777188764, ExAC 0.01%). This variant has been observed in individuals affected with familial hypercholesterolemia (PMID: 20018285, 25461735, Invitae). ClinVar contains an entry for this variant (Variation ID: 251996). 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, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Variants that disrupt the p.Arg574 amino acid residue in LDLR have been observed in affected individuals (PMID: 11462246, 19446849, 26892515, 20018285, 25461735, Invitae). This suggests that it is a clinically significant residue, and that other variants that disrupt this residue are likely to be causative of disease. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Color Health, Inc RCV000791382 SCV001355014 likely pathogenic Familial hypercholesterolemia 2019-10-14 criteria provided, single submitter clinical testing
New York Genome Center RCV001256078 SCV001432865 likely pathogenic Hypercholesterolemia 2020-02-11 criteria provided, single submitter clinical testing The c.1721G>A, p.Arg574His variant in the LDLR gene has been observed in individuals affected with familial hypercholesterolemia [PMID: 20018285; PMID: 25461735; PMID: 23375686]. The variant has 0.0031% allele frequency in the gnomAD database (9 out of 282,858 heterozygous alleles), indicating this is a rare allele. In silico tools predict that this variant is likely to be disruptive[https://useast.ensembl.org/info/docs/tools/vep/index.html]. Variants that disrupt the p.Arg574 amino acid residue in LDLR have been observed in individuals affected with familial hypercholesterolemia [PMID: 20018285; PMID: 25461735; PMCID: PMC4766367; PMID: 19446849; PMID: 11462246]. This suggests that it is a clinically significant residue, and that other variants that disrupt this residue are likely to be causative of disease. Based on the available evidence, the c.1721G>A, p.Arg574His variant in the LDLR gene is classified as likely pathogenic.

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