ClinVar Miner

Submissions for variant NM_000271.5(NPC1):c.2974G>T (p.Gly992Trp) (rs80358254)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000020230 SCV000220581 pathogenic Niemann-Pick disease type C1 2014-08-07 criteria provided, single submitter literature only
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000723413 SCV000700313 uncertain significance not provided 2016-10-25 criteria provided, single submitter clinical testing
Invitae RCV000020230 SCV000941919 pathogenic Niemann-Pick disease type C1 2018-12-31 criteria provided, single submitter clinical testing This sequence change replaces glycine with tryptophan at codon 992 of the NPC1 protein (p.Gly992Trp). The glycine residue is highly conserved and there is a large physicochemical difference between glycine and tryptophan. This variant is present in population databases (rs80358254, ExAC 0.001%). This variant has been observed in several individuals affected with Niemann-Pick disease type C (NPC), and it has been observed to segregate with NPC in families (PMID: 9634529, 26666848, 16778374, 20718790, 11545687, 28222799). ClinVar contains an entry for this variant (Variation ID: 2960). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant disrupts the p.Gly992 amino acid residue in NPC1. Other variant(s) that disrupt this residue have been observed in individuals with NPC1-related conditions (PMID: 11333381, 16126423, 26984608), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics RCV000020230 SCV001163436 pathogenic Niemann-Pick disease type C1 criteria provided, single submitter clinical testing
OMIM RCV000003094 SCV000023252 pathogenic Niemann-Pick disease, type D 1998-07-01 no assertion criteria provided literature only
GeneReviews RCV000020230 SCV000040574 pathologic Niemann-Pick disease type C1 2008-07-22 no assertion criteria provided curation Converted during submission to Pathogenic.
SingHealth Duke-NUS Institute of Precision Medicine RCV000020230 SCV000853138 likely pathogenic Niemann-Pick disease type C1 2017-06-07 no assertion criteria provided curation

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