ClinVar Miner

Submissions for variant NM_000271.5(NPC1):c.1436G>A (p.Cys479Tyr) (rs1555636659)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000649020 SCV000770841 uncertain significance Niemann-Pick disease type C1 2017-10-13 criteria provided, single submitter clinical testing This sequence change replaces cysteine with tyrosine at codon 479 of the NPC1 protein (p.Cys479Tyr). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and tyrosine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals affected with Niemann-Pick disease, being found in trans with a likely pathogenic variant in one of these cases (PMID: 16098014, 20718790, Invitae). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000728564 SCV000856156 uncertain significance not provided 2017-08-10 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000649020 SCV000915802 uncertain significance Niemann-Pick disease type C1 2018-11-15 criteria provided, single submitter clinical testing The NPC1 c.1436G>A (p.Cys479Tyr) missense variant has been reported in two studies and is found in two individuals with Niemann-Pick disease type C, including one each in a compound heterozygous state with a second missense variant and in a heterozygous state (Fernandez-Valero et al. 2005; Macias-Vidal et al. 2011). The p.Cys479Tyr variant was absent from 100 controls and is not found in the 1000 Genomes Project, the Exome Sequencing Project, the Exome Aggregation Consortium or the Genome Aggregation Database. Based on the limited evidence, the p.Cys479Tyr 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.
Baylor Genetics RCV000649020 SCV001163439 likely pathogenic Niemann-Pick disease type C1 criteria provided, single submitter clinical testing

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