ClinVar Miner

Submissions for variant NM_000527.4(LDLR):c.1381G>A (p.Gly461Ser) (rs193922568)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Integrated Genetics/Laboratory Corporation of America RCV000030128 SCV000052783 likely pathogenic Familial hypercholesterolemia 1 2011-08-18 criteria provided, single submitter curation Converted during submission to Likely pathogenic.
Invitae RCV001050334 SCV001214433 uncertain significance Familial hypercholesterolemia 2019-11-19 criteria provided, single submitter clinical testing This sequence change replaces glycine with serine at codon 461 of the LDLR protein (p.Gly461Ser). The glycine residue is weakly conserved and there is a small physicochemical difference between glycine and serine. This variant is present in population databases (rs193922568, ExAC 0.02%). This variant has not been reported in the literature in individuals with LDLR-related conditions. ClinVar contains an entry for this variant (Variation ID: 36456). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The serine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Color RCV001050334 SCV001353773 likely benign Familial hypercholesterolemia 2019-05-20 criteria provided, single submitter clinical testing
Institute of Human Genetics, University of Leipzig Medical Center RCV000030128 SCV001429519 uncertain significance Familial hypercholesterolemia 1 2017-10-19 criteria provided, single submitter clinical testing
Broad Institute Rare Disease Group,Broad Institute RCV000030128 SCV001423096 uncertain significance Familial hypercholesterolemia 1 2020-01-29 no assertion criteria provided curation The p.Gly461Ser variant in LDLR has been reported in at least one individual with Familial Hypercholesterolemia in ClinVar (Variation ID: 36456), and has been identified in 0.003266% (1/30614) of South Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs193922568). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a carrier frequency. Please note that for diseases with clinical variability, or reduced penetrance, pathogenic variants may be present at a low frequency in the general population. This variant has also been reported likely pathogenic in ClinVar (Variation ID: 36456). Computational prediction tools and conservation analyses suggest that this variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. One VUS at the same position, p.Gly461Cys, has been reported in association with disease in ClinVar (Variation ID: 183113). This variant may be in a functional domain involved in cell signaling (PMID: 23815734, 16465405). In summary, the clinical significance of the p.Gly461Ser variant is uncertain. ACMG/AMP Criteria applied: PM1_Supporting, PM2, BP4 (Richards 2015).

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