ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.1247G>T (p.Arg416Leu)

dbSNP: rs773658037
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
LDLR-LOVD, British Heart Foundation RCV000237152 SCV000295327 likely pathogenic Hypercholesterolemia, familial, 1 2016-03-25 criteria provided, single submitter literature only
Revvity Omics, Revvity RCV000237152 SCV002022668 likely pathogenic Hypercholesterolemia, familial, 1 2020-03-23 criteria provided, single submitter clinical testing
Invitae RCV003581618 SCV004298350 likely pathogenic Familial hypercholesterolemia 2024-01-13 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 416 of the LDLR protein (p.Arg416Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with familial hypercholesterolemia (PMID: 20538126). This variant is also known as R395L. ClinVar contains an entry for this variant (Variation ID: 251754). 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.Arg416 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9104431, 9259195, 11196104, 11668640, 14974088, 17539906, 18700895, 20538126, 20663204, 21310417, 21376320, 23375686, 25378237, 25921077, 25962062, 26892515). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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.
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum RCV000237152 SCV000606375 pathogenic Hypercholesterolemia, familial, 1 no assertion criteria provided research

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