ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.1209C>A (p.Phe403Leu)

dbSNP: rs777903106
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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000685044 SCV000812516 pathogenic Familial hypercholesterolemia 2019-11-28 criteria provided, single submitter clinical testing A different variant (c.1207T>C) giving rise to the same protein effect observed here (p.Phe403Leu) has been reported in several individuals affected with familial hypercholesterolemia (PMID: 15359125, 10447263), indicating that this residue may be critical for protein function. This variant is also known as p.Phe382Leu in the literature. For these reasons, this variant has been classified as Pathogenic. 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. This variant has been observed in an individual affected with hypercholesterolemia (Invitae). ClinVar contains an entry for this variant (Variation ID: 565474). This variant is not present in population databases (ExAC no frequency). This sequence change replaces phenylalanine with leucine at codon 403 of the LDLR protein (p.Phe403Leu). The phenylalanine residue is highly conserved and there is a small physicochemical difference between phenylalanine and leucine.

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