ClinVar Miner

Submissions for variant NM_000527.4(LDLR):c.1067A>T (p.Asp356Val) (rs879254777)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Color Health, Inc RCV001187845 SCV001354737 likely pathogenic Familial hypercholesterolemia 2019-01-17 criteria provided, single submitter clinical testing
Invitae RCV001187845 SCV001385849 likely pathogenic Familial hypercholesterolemia 2019-09-16 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with valine at codon 356 of the LDLR protein (p.Asp356Val). The aspartic acid residue is highly conserved and there is a large physicochemical difference between aspartic acid and valine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in several individuals with clinical features of familial hypercholesterolemia (PMID: 30745730, Invitae). ClinVar contains an entry for this variant (Variation ID: 440623). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant disrupts the p.Asp356 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9104431, 15998910). 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 RCV000508971 SCV000606317 pathogenic Familial hypercholesterolemia 1 no assertion criteria provided research

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