ClinVar Miner

Submissions for variant NM_000271.5(NPC1):c.530G>A (p.Cys177Tyr)

gnomAD frequency: 0.00001  dbSNP: rs80358252
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000003108 SCV000221079 likely pathogenic Niemann-Pick disease, type C1 2015-01-23 criteria provided, single submitter literature only
Ambry Genetics RCV000623140 SCV000742791 likely pathogenic Inborn genetic diseases 2017-08-18 criteria provided, single submitter clinical testing
Eurofins Ntd Llc (ga) RCV000730873 SCV000858640 pathogenic not provided 2017-12-18 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV000003108 SCV001579549 pathogenic Niemann-Pick disease, type C1 2023-10-28 criteria provided, single submitter clinical testing This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 177 of the NPC1 protein (p.Cys177Tyr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Niemann-Pick type C (PMID: 11479732, 16098014, 28222799). ClinVar contains an entry for this variant (Variation ID: 2974). 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%. For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV000730873 SCV001795828 pathogenic not provided 2022-05-04 criteria provided, single submitter clinical testing In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 11479732, 12955717, 25131710, 12974729, 20301473, 19744920, 16098014, 20826119, 16126423, 15459971, 10521297, 425535, 30820861, 30985853, 31589614, 20718790, 28222799, 22572546, 20525256)
New York Genome Center RCV000003108 SCV002099148 pathogenic Niemann-Pick disease, type C1 2021-04-02 criteria provided, single submitter clinical testing The c.530G>A, p.Cys177Tyr missense variant identified in NPC1 has been reported as homozygous or compound heterozygous in multiple patients with severe infantile, late infantile, and juvenile Niemann-Pick disease type C [PMID: 11479732; PMID: 32709131; PMID: 20718790]. This variant has two heterozygous alleles in the gnomAD v3 database, indicating this is a rare allele and in silico tools predict a deleterious effect. Based on the available evidence, the inherited variant c.530G>A, p.Cys177Tyr in the NPC1 gene is classified as pathogenic.
OMIM RCV000003108 SCV000023266 pathogenic Niemann-Pick disease, type C1 2001-07-01 no assertion criteria provided literature only
GeneReviews RCV000003108 SCV000040579 not provided Niemann-Pick disease, type C1 no assertion provided literature only

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