Submissions for variant NM_000271.5(NPC1):c.3100G>A (p.Gly1034Arg)

dbSNP: rs2058637844

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Breda Genetics srl	RCV001248808	SCV001364284	pathogenic	Niemann-Pick disease, type C1	2020-06-24	criteria provided, single submitter	clinical testing	The variant c.3100G>A (p.Gly1034Arg) in the NPC1 gene has not been previously reported neither in Clinvar nor in the LOVD database, however it has been firstly described by Yang et al. (2005) in a patient with Niemann-Pick disease. The authors did not identified a second pathogenic variant in that patient (PMID: 15774455). Recently, Klünder et al. identified this variant in a patient who also had another missense variant in the NPC1 gene (PMID: 26108224). Moreover, this missense variant falls in a region where other pathogenic missense variants had already been reported (Clinvar).
Invitae	RCV001248808	SCV002285471	likely pathogenic	Niemann-Pick disease, type C1	2022-09-12	criteria provided, single submitter	clinical testing	This missense change has been observed in individual(s) with Niemann-Pick Type C and/or spinocerebellar ataxia with cognitive decline (PMID: 15774455, 31743419). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. 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. ClinVar contains an entry for this variant (Variation ID: 972703). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 1034 of the NPC1 protein (p.Gly1034Arg).
Molecular Diagnostics Laboratory, M Health Fairview: University of Minnesota	RCV001248808	SCV002507307	likely pathogenic	Niemann-Pick disease, type C1	2022-03-01	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003399019	SCV004121112	likely pathogenic	NPC1-related condition	2022-10-24	criteria provided, single submitter	clinical testing	The NPC1 c.3100G>A variant is predicted to result in the amino acid substitution p.Gly1034Arg. This variant was reported in homozygous and compound heterozygous state in several individuals with Niemann-Pick disease (Yang et al 2005. PubMed ID: 15774455; Abtahi et al 2022. PubMed ID: 35086560; Klunder et al. 2015. PubMed ID: 26108224). Majority of these patients had filipin staining performed (confirmation of intravesicular cholesterol storage that serves as clinical confirmation of NPC diagnosis), which was positive in all tested patients. This variant was also found in compound heterozygous state in patient with spinocerebellar ataxia (Guan et al 2019. PubMed ID: 31743419). This variant is reported as pathogenic and likely pathogenic in ClinVar. This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as likely pathogenic.