ClinVar Miner

Submissions for variant NM_000271.5(NPC1):c.3763G>A (p.Val1255Ile)

gnomAD frequency: 0.00001  dbSNP: rs755597503
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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 RCV001917075 SCV002194845 uncertain significance Niemann-Pick disease, type C1 2021-08-09 criteria provided, single submitter clinical testing This sequence change replaces valine with isoleucine at codon 1255 of the NPC1 protein (p.Val1255Ile). The valine residue is weakly conserved and there is a small physicochemical difference between valine and isoleucine. This variant is present in population databases (rs755597503, ExAC 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 not expected to disrupt NPC1 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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