ClinVar Miner

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

gnomAD frequency: 0.00002  dbSNP: rs28942105
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000003093 SCV000957635 pathogenic Niemann-Pick disease, type C1 2024-01-21 criteria provided, single submitter clinical testing This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 1156 of the NPC1 protein (p.Asn1156Ser). This variant is present in population databases (rs28942105, gnomAD 0.004%). This missense change has been observed in individuals with Niemann-Pick type C (PMID: 9211849, 16098014, 17160617, 23430855, 26666848, 27900365, 28710748). ClinVar contains an entry for this variant (Variation ID: 2959). 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%. This variant disrupts the p.Asn1156 amino acid residue in NPC1. Other variant(s) that disrupt this residue have been observed in individuals with NPC1-related conditions (PMID: 9211849, 16098014, 17160617, 23430855, 26666848, 27900365), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics RCV000003093 SCV001163433 pathogenic Niemann-Pick disease, type C1 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV003114174 SCV003800706 pathogenic Niemann-Pick disease, type C 2023-01-24 criteria provided, single submitter clinical testing Variant summary: NPC1 c.3467A>G (p.Asn1156Ser) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 248932 control chromosomes. c.3467A>G has been reported in the literature as a biallelic homozygous or compound heterozygous genotype in multiple individuals affected with Niemann-Pick Disease Type C (example, PMID: 9211849, 19744920, 26981555, 12401890). These data indicate that the variant is very likely to be associated with disease. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Mayo Clinic Laboratories, Mayo Clinic RCV003480016 SCV004226691 pathogenic not provided 2022-06-03 criteria provided, single submitter clinical testing PP3, PP4, PM2, PM3, PM5, PS3, PS4
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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