ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.1435C>G (p.Leu479Val)

gnomAD frequency: 0.00001  dbSNP: rs1254928151
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV002395230 SCV002702842 uncertain significance Cardiovascular phenotype 2019-11-01 criteria provided, single submitter clinical testing The p.L479V variant (also known as c.1435C>G), located in coding exon 10 of the LDLR gene, results from a C to G substitution at nucleotide position 1435. The leucine at codon 479 is replaced by valine, an amino acid with highly similar properties, and is located in the EGF precursor-like domain. Other variants affecting this codon (p.L479P, c.1436T>C and p.L479Q, c.1436T>A) have been reported in association with familial hypercholesterolemia (Heath KE et al. Eur. J. Hum. Genet., 2001 Apr;9:244-52 (reported as p.L458P); Fairoozy RH et al. Sci Rep, 2017 12;7:17087). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae RCV002524933 SCV003277309 pathogenic Familial hypercholesterolemia 2023-12-31 criteria provided, single submitter clinical testing This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 479 of the LDLR protein (p.Leu479Val). This variant is present in population databases (no rsID available, gnomAD 0.008%). This missense change has been observed in individuals with clinical features of familial hypercholesterolemia (Invitae). ClinVar contains an entry for this variant (Variation ID: 440643). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt LDLR protein function with a positive predictive value of 95%. This variant disrupts the p.Leu479 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been observed in individuals with LDLR-related conditions (PMID: 11313767, 29213121; Invitae), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum RCV000508973 SCV000606426 pathogenic Hypercholesterolemia, familial, 1 no assertion criteria provided research

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