Submissions for variant NM_000271.5(NPC1):c.2848G>A (p.Val950Met)

gnomAD frequency: 0.00001  dbSNP: rs120074135

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000212760	SCV000208908	pathogenic	not provided	2019-08-06	criteria provided, single submitter	clinical testing	Reported previously in association with Niemann-Pick disease, type C (NPC) (Millat et al., 2001; Millat et al., 2005; Sevin et al. 2007; Garver et al. 2010). Two patients with NPC who were apparently homozygous for the V950M variant had adult onset of neurological symptoms (Millat et al., 2001; Sevin et al. 2007); Missense variants in this gene are often considered pathogenic (Stenson et al., 2014); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 15465421, 26666848, 19744920, 16126423, 26984608, 11333381, 17003072, 27900365)
Counsyl	RCV000003105	SCV000221112	likely pathogenic	Niemann-Pick disease, type C1	2015-02-03	criteria provided, single submitter	literature only
Invitae	RCV000003105	SCV000770848	pathogenic	Niemann-Pick disease, type C1	2023-12-02	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 950 of the NPC1 protein (p.Val950Met). This variant is present in population databases (rs120074135, gnomAD 0.007%). This missense change has been observed in individuals with Niemann-Pick disease type C (PMID: 11333381, 17003072, 26984608, 27900365). ClinVar contains an entry for this variant (Variation ID: 2971). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on NPC1 protein function. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on NPC1 function (PMID: 28193631, 30923329, 31699992). This variant disrupts the p.Val950 amino acid residue in NPC1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 25236789, 26981555). 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.
Fulgent Genetics, Fulgent Genetics	RCV000003105	SCV000893487	likely pathogenic	Niemann-Pick disease, type C1	2022-05-05	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000003105	SCV001528305	pathogenic	Niemann-Pick disease, type C1	2018-03-14	criteria provided, single submitter	clinical testing	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. The c.2848G>A (p.V950M) variant has been previously reported in multiple patients with adult-onset Niemann-Pick disease and variant biochemical phenotype [PMID 11333381, 16126423, 26984608, 27900365]
Revvity Omics, Revvity	RCV000003105	SCV003824132	pathogenic	Niemann-Pick disease, type C1	2022-06-06	criteria provided, single submitter	clinical testing
OMIM	RCV000003105	SCV000023263	pathogenic	Niemann-Pick disease, type C1	2001-06-01	no assertion criteria provided	literature only
Shendure Lab, University of Washington	RCV000003105	SCV000297807	pathogenic	Niemann-Pick disease, type C1	2016-08-01	no assertion criteria provided	clinical testing	patient had late-onset NPC
Natera, Inc.	RCV000003105	SCV002095180	pathogenic	Niemann-Pick disease, type C1	2021-08-03	no assertion criteria provided	clinical testing