ClinVar Miner

Submissions for variant NM_000527.4(LDLR):c.653del (p.Gly218fs) (rs137853966)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
LDLR-LOVD, British Heart Foundation RCV000237824 SCV000294852 pathogenic Familial hypercholesterolemia 1 2016-03-25 criteria provided, single submitter literature only
Robarts Research Institute,Western University RCV000237824 SCV000484795 likely pathogenic Familial hypercholesterolemia 1 criteria provided, single submitter clinical testing
Invitae RCV001201376 SCV000627045 pathogenic Familial hypercholesterolemia 2019-08-26 criteria provided, single submitter clinical testing This sequence change deletes 1 nucleotide from exon 4 of the LDLR mRNA (c.653delG), causing a frameshift at codon 218. This creates a premature translational stop signal (p.Gly218Valfs*47) and is expected to result in an absent or disrupted protein product. Loss-of-function variants in LDLR are known to be pathogenic. This particular variant has been reported in the literature in several individuals affected with hypercholesterolemia (PMID: 7649546, 27765764). This variant is also known in the literature as c.652delG. For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV000058918 SCV000709934 pathogenic not provided 2018-02-14 criteria provided, single submitter clinical testing The c.653delG pathogenic variant in the LDLR gene (also reported as 1 bp deletion: G in codon 197, 652delG, and G197V->X243 due to alternate nomenclature) has been reported previously in at least three unrelated individuals with FH, and appears to be segregating with disease in two relatives of one of these individuals (Giesel et al., 1995; Wang et al., 2001; Biesecker et al., 2009). Furthermore, the c.653delG variant has not been observed in large population cohorts (Lek et al., 2016). This variant causes a shift in reading frame starting at codon glycine (Gly) 218, changing it to a valine (Val), and creating a premature stop codon at position 47 of the new reading frame, denoted p.Gly218ValfsX47. This pathogenic variant is expected to result in either an abnormal, truncated protein product or loss of protein from this allele through nonsense-mediated mRNA decay. Moreover, other frameshift variants in the LDLR gene have been reported in Human Gene Mutation Database in association with FH (Stenson et al., 2014), indicating that loss of function is a mechanism of disease for this gene.
SNPedia RCV000058918 SCV000090439 not provided not provided no assertion provided not provided

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