Submissions for variant NM_000271.5(NPC1):c.2932C>T (p.Arg978Cys)

gnomAD frequency: 0.00001  dbSNP: rs28942108

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000413627	SCV000331826	pathogenic	not provided	2017-11-21	criteria provided, single submitter	clinical testing
Counsyl	RCV000003110	SCV000485655	likely pathogenic	Niemann-Pick disease, type C1	2016-01-21	criteria provided, single submitter	clinical testing
GeneDx	RCV000413627	SCV000490667	pathogenic	not provided	2019-10-21	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek et al., 2016); The majority of missense variants in this gene are considered pathogenic (Stenson et al., 2014); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Observed in individuals heterozygous for R978C and another pathogenic variant in NPC1 in association with variant Niemann-Pick disease type C biochemical phenotype and highly variable symptoms and age of onset, ranging from neonatal liver disease to gait ataxia and dysarthria at the age of 20 (Sun et al., 2001; Macias-Vidal et al., 2011; Di Leo et al., 2004; Abela et al., 2014; Perez-Poyato et al., 2012); This variant is associated with the following publications: (PMID: 22750297, 11349231, 15459971, 11479732, 26984608, 24035292, 20718790, 23433426, 28332184, 25425405, 31639011, 32138288, 31589614)
Baylor Genetics	RCV000003110	SCV000807222	pathogenic	Niemann-Pick disease, type C1	2017-09-01	criteria provided, single submitter	clinical testing	This variant has been previously reported as disease-causing and was found once in our laboratory in trans with a missense variant in a 15-year-old female with Niemann-Pick Type C
Labcorp Genetics (formerly Invitae), Labcorp	RCV000003110	SCV000826854	pathogenic	Niemann-Pick disease, type C1	2023-05-31	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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: 2976). This missense change has been observed in individual(s) with Niemann-Pick disease type C (NPC) (PMID: 11349231, 11479732, 15459971, 20718790, 22750297, 23427322, 23433426, 23774949, 26984608; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs28942108, gnomAD 0.01%). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 978 of the NPC1 protein (p.Arg978Cys).
Genetic Services Laboratory, University of Chicago	RCV000413627	SCV002069055	pathogenic	not provided	2017-12-01	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV004017222	SCV004848141	pathogenic	Niemann-Pick disease, type C	2017-11-24	criteria provided, single submitter	clinical testing	The p.Arg978Cys variant in NPC1 has been reported in 1 heterozygous individual with Parkinson disease and 9 individuals with the variant form and/or juvenile/adult onset of Niemann-Pick disease type C (Di Leo 2004, Kluenemann 2013, Macia-Vidal 2011, Perez-Poyato 2012, Riberio 2001, Schicks 2013, Sedel 2016, Stampfer 2013, Sun 2001). All of the 9 individuals also carried another variant in NPC1 in trans, with at least 2 being known disease-causing variants. It also segregated along with another variant in NPC1 in trans in 4 affected relatives from 3 families (Di Leo 2004, Kluenemann 2013). This variant has also been reported in ClinVar (Variation ID 2976). p.Arg978Cys variant has been identified in 1/9848 of Ashkenazi Jewish and 2/111684 European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; rs28942108). Although this variant has been seen in the general population, its frequency is low enough to be consistent with carrier frequency for Niemann-Pick disease type C. Computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. In summary, this variant meets criteria to be classified as pathogenic for the variant form of Niemann-Pick disease type C in an autosomal recessive manner. ACMG/AMP Criteria applied: PM2; PM3_VeryStrong; PP1.
OMIM	RCV000003110	SCV000023268	pathogenic	Niemann-Pick disease, type C1	2001-07-01	no assertion criteria provided	literature only