ClinVar Miner

Submissions for variant NM_000271.5(NPC1):c.2692G>A (p.Asp898Asn)

gnomAD frequency: 0.00004  dbSNP: rs528841924
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000506380 SCV000604563 uncertain significance not specified 2016-10-06 criteria provided, single submitter clinical testing
Illumina Laboratory Services, Illumina RCV000779242 SCV000915798 uncertain significance Niemann-Pick disease, type C1 2018-11-19 criteria provided, single submitter clinical testing The NPC1 c.2692G>A (p.Asp898Asn) variant has been described in a single study in which it was found in a compound heterozygous state with a frameshift variant in one individual with Niemann-Pick disease (Abela et al. 2014). Control data are unavailable for this variant, which is reported at a frequency of 0.000047 in the European (non-Finnish) population of the Exome Aggregation Consortium. Based on the evidence, the p.Asp898Asn variant is classified as a variant of unknown significance but suspicious for pathogenicity for Niemann-Pick disease, type C. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Labcorp Genetics (formerly Invitae), Labcorp RCV000779242 SCV001497275 uncertain significance Niemann-Pick disease, type C1 2022-05-09 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 898 of the NPC1 protein (p.Asp898Asn). This variant is present in population databases (rs528841924, gnomAD 0.006%). This missense change has been observed in individual(s) with Niemann-Pick disease type C (PMID: 25425405). ClinVar contains an entry for this variant (Variation ID: 440008). 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.
GeneDx RCV001755755 SCV001986192 uncertain significance not provided 2021-04-29 criteria provided, single submitter clinical testing Reported previously in association with Niemann-Pick disease, type C (NPC) in a patient who also harbored a second variant in the NPC1 gene, however phase was unknown (Abela et al., 2014); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 31754021, 25425405)
Natera, Inc. RCV000779242 SCV002095186 uncertain significance Niemann-Pick disease, type C1 2020-10-06 no assertion criteria provided clinical testing

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