ClinVar Miner

Submissions for variant NM_000271.5(NPC1):c.1351G>A (p.Glu451Lys) (rs781065429)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000670724 SCV000795617 uncertain significance Niemann-Pick disease type C1 2017-11-10 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000670724 SCV000915803 uncertain significance Niemann-Pick disease type C1 2017-09-11 criteria provided, single submitter clinical testing The NPC1 c.1351G>A (p.Glu451Lys) variant has been reported in a compound heterozygous state with the same second missense variant in seven individuals from two families, a pair of siblings in one family and five siblings in the second family (Tarugi et al. 2002; Romanello et al. 2016). While all individuals were noted to have Niemann-Pick disease (NPCD), four siblings were 'not classified' due to absence of neurological symptoms (Romanello et al. 2016). In addition, the five siblings exhibited a variant biochemical phenotype based on filipin staining and specific types of oxysterols were observed at either below or slightly above the cut-off noted in patients with NPCD (Romanello et al. 2016). The p.Glu451Lys variant was also identified in a heterozygous state in one individual with the early infantile form who also displayed the variant biochemical phenotype; however, in this individual, a second variant was not identified (De Castro-Oros et al. 2017). The p.Glu451Lys variant was absent from 300 control alleles and is reported at a frequency of 0.000305 in the South Asian population of the Exome Aggregation Consortium. Functional studies of the variant have not been conducted, but it results in a nonconservative substitution of a highly conserved amino acid (Tarugi et al. 2002). Based on the collective evidence, the p.Glu451Lys 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.
Invitae RCV000670724 SCV001390377 likely pathogenic Niemann-Pick disease type C1 2019-06-23 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 451 of the NPC1 protein (p.Glu451Lys). The glutamic acid residue is moderately conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is present in population databases (rs781065429, ExAC 0.03%). This variant has been observed to segregate with Niemann-Pick type C in a family (PMID: 26790753). ClinVar contains an entry for this variant (Variation ID: 554990). 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 tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.
Mayo Clinic Genetic Testing Laboratories,Mayo Clinic RCV000675577 SCV000801268 uncertain significance not provided 2017-12-01 no assertion criteria provided clinical testing

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