ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.599T>G (p.Phe200Cys)

dbSNP: rs879254586
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
LDLR-LOVD, British Heart Foundation RCV000237736 SCV000294812 uncertain significance Hypercholesterolemia, familial, 1 2016-03-25 criteria provided, single submitter literature only
PreventionGenetics, part of Exact Sciences RCV003391006 SCV004119713 uncertain significance LDLR-related disorder 2023-04-05 criteria provided, single submitter clinical testing The LDLR c.599T>G variant is predicted to result in the amino acid substitution p.Phe200Cys. This variant is also described using legacy nomenclature as p.Phe179Cys, has been reported in individuals with Hypercholesterolemia (Chiou et al. 2010. PubMed ID: 20538126; Chan et al. 2018. PubMed ID: 30592178. Table S1; Huang et al. 2021. PubMed ID: 33994402). Different missense variants in the same codon (p.Phe200Leu; p.Phe200Ile) have been reported in individuals with Hypercholesterolemia (Nauck et al. 2001. PubMed ID: 11462246; ClinVar ID: 251313). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Labcorp Genetics (formerly Invitae), Labcorp RCV003581604 SCV004298326 pathogenic Familial hypercholesterolemia 2024-02-13 criteria provided, single submitter clinical testing This sequence change replaces phenylalanine, which is neutral and non-polar, with cysteine, which is neutral and slightly polar, at codon 200 of the LDLR protein (p.Phe200Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 20538126, 30592178, 33994402). This variant is also known as F179C. ClinVar contains an entry for this variant (Variation ID: 251314). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on LDLR protein function. This variant disrupts the p.Phe200 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been observed in individuals with LDLR-related conditions (PMID: 11462246), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.

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