ClinVar Miner

Submissions for variant NM_000271.5(NPC1):c.2593T>A (p.Ser865Thr)

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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 RCV003825754 SCV004623220 likely pathogenic Niemann-Pick disease, type C1 2023-10-31 criteria provided, single submitter clinical testing This sequence change replaces serine, which is neutral and polar, with threonine, which is neutral and polar, at codon 865 of the NPC1 protein (p.Ser865Thr). This variant is present in population databases (no rsID available, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with NPC1-related conditions. 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 NPC1 protein function with a positive predictive value of 95%. This variant disrupts the p.Ser865 amino acid residue in NPC1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16098014, 16126423). 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.

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