ClinVar Miner

Submissions for variant NM_000271.5(NPC1):c.2932C>T (p.Arg978Cys) (rs28942108)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 6
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics 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 2016-06-13 criteria provided, single submitter clinical testing The R978C missense variant has been previously reported several times in association with a variantNiemann-Pick disease type C (NPC) biochemical phenotype (Sun et al., 2001; Macias-Vidal et al.,2011; Di Leo et al., 2004). Individuals who were heterozygous for R978C and another pathogenicvariant in NPC1 had a highly variable age of onset of symptoms and presentation ranging fromneonatal liver disease to gait ataxia and dysarthria at the age of 20 (Sun et al., 2001; Macias-Vidal etal., 2011; Di Leo et al., 2004; Abela et al., 2014; Perez-Poyato et al., 2012). Therefore, we interpretR978C to be a pathogenic variant.
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
Invitae RCV000003110 SCV000826854 likely pathogenic Niemann-Pick disease type C1 2018-03-22 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 978 of the NPC1 protein (p.Arg978Cys). The arginine residue is moderately conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs28942108, ExAC 0.003%). This variant has been reported in combination with another NPC1 variant in individuals affected with Niemann-Pick disease type C (NPC) (PMID: 11479732, 15459971, 20718790, 26984608, 11349231, 23427322 , 23774949, 22750297, 23433426). One of these individuals was reported to be an "NPC variant", one of a small number of affected individuals who have near-normal biochemical tests (PMID: 11349231). ClinVar contains an entry for this variant (Variation ID: 2976). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C15"). 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.
OMIM RCV000003110 SCV000023268 pathogenic Niemann-Pick disease type C1 2001-07-01 no assertion criteria provided literature only

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.