ClinVar Miner

Submissions for variant NM_000271.5(NPC1):c.1166G>T (p.Arg389Leu)

dbSNP: rs373751051
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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 RCV001989546 SCV002281604 likely pathogenic Niemann-Pick disease, type C1 2021-11-11 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 389 of the NPC1 protein (p.Arg389Leu). 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. This variant disrupts the p.Arg389 amino acid residue in NPC1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12955717; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. This missense change has been observed in individual(s) with Niemann-Pick disease type C (PMID: 19252935, 32138288). This variant is not present in population databases (gnomAD no frequency).

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