ClinVar Miner

Submissions for variant NM_000271.5(NPC1):c.3467A>G (p.Asn1156Ser) (rs28942105)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000003093 SCV000957635 likely pathogenic Niemann-Pick disease type C1 2018-08-07 criteria provided, single submitter clinical testing This sequence change replaces asparagine with serine at codon 1156 of the NPC1 protein (p.Asn1156Ser). The asparagine residue is highly conserved and there is a small physicochemical difference between asparagine and serine. This variant is present in population databases (rs28942105, ExAC 0.004%). This variant has been observed in combination with another NPC variant in individuals affected with Niemann-Pick type C (PMID: 9211849, 23430855, 26666848, 16098014, 17160617, 27900365). ClinVar contains an entry for this variant (Variation ID: 2959). 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. The observation of one or more missense substitutions at this codon (p.Asn1156Ser and p.Asn1156Ile) in affected individuals suggests that this may be a clinically significant residue (PMID: 16098014, 9211849, 23430855, 26666848, 17160617, 27900365). 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.
OMIM RCV000003093 SCV000023251 pathogenic Niemann-Pick disease type C1 1997-07-11 no assertion criteria provided literature only
Shendure Lab,University of Washington RCV000003093 SCV000297806 pathogenic Niemann-Pick disease type C1 2016-08-01 no assertion criteria provided clinical testing patient had late-onset NPC

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