ClinVar Miner

Submissions for variant NM_000271.5(NPC1):c.1421C>T (p.Pro474Leu)

gnomAD frequency: 0.00002  dbSNP: rs372445155
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Centre for Mendelian Genomics, University Medical Centre Ljubljana RCV000415065 SCV000492759 pathogenic Cataplexy; Cerebellar ataxia; Cognitive impairment; Headache; Speech apraxia; Postural instability 2014-10-07 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV000823177 SCV000964026 pathogenic Niemann-Pick disease, type C1 2023-11-25 criteria provided, single submitter clinical testing This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 474 of the NPC1 protein (p.Pro474Leu). This variant is present in population databases (rs372445155, gnomAD 0.007%). This missense change has been observed in individual(s) with Niemann-Pick type C (PMID: 12401890, 16086131, 16098014). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 374049). 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%. For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV004591143 SCV005081305 pathogenic not provided 2024-01-08 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 12401890, 16086131, 34426522, 31743419, 33598405, 30119649, 35892469, 32138288)
Natera, Inc. RCV000823177 SCV001455875 pathogenic Niemann-Pick disease, type C1 2020-09-16 no assertion criteria provided clinical testing

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