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

dbSNP: rs80358254

Total submissions: 11

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
Eurofins Ntd Llc (ga)	RCV000723413	SCV000700313	uncertain significance	not provided	2016-10-25	criteria provided, single submitter	clinical testing
Invitae	RCV000020230	SCV000941919	pathogenic	Niemann-Pick disease, type C1	2024-01-27	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with tryptophan, which is neutral and slightly polar, at codon 992 of the NPC1 protein (p.Gly992Trp). This variant is present in population databases (rs80358254, gnomAD 0.003%). This missense change has been observed in individuals with Niemann-Pick disease type C (PMID: 9634529, 11545687, 16778374, 20718790, 26666848, 28222799). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 2960). 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.Gly992 amino acid residue in NPC1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11333381, 16126423, 26984608). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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
GeneDx	RCV000723413	SCV001781732	pathogenic	not provided	2022-10-10	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 12955717, 11479732, 16778374, 12401890, 10521290, 11545687, 20718790, 9634529, 16126423, 24001525, 26666848, 29961769, 9245994, 31497485, 32222928, 20301473, 32138288, 34535129)
Revvity Omics, Revvity	RCV000020230	SCV003815154	likely pathogenic	Niemann-Pick disease, type C1	2022-03-15	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	not provided	Niemann-Pick disease, type C1		no assertion provided	literature only
SingHealth Duke-NUS Institute of Precision Medicine	RCV000020230	SCV000853138	likely pathogenic	Niemann-Pick disease, type C1	2017-06-07	no assertion criteria provided	curation
Natera, Inc.	RCV000020230	SCV001453837	pathogenic	Niemann-Pick disease, type C1	2020-09-16	no assertion criteria provided	clinical testing
Hereditary Research Laboratory, Bethlehem University	RCV000020230	SCV001653519	likely pathogenic	Niemann-Pick disease, type C1	2021-06-02	no assertion criteria provided	clinical testing