Submissions for variant NM_000271.5(NPC1):c.873G>T (p.Trp291Cys)

gnomAD frequency: 0.00045  dbSNP: rs138151007

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000675579	SCV000344223	uncertain significance	not provided	2018-02-23	criteria provided, single submitter	clinical testing
Invitae	RCV000649022	SCV000770843	uncertain significance	Niemann-Pick disease, type C1	2022-11-01	criteria provided, single submitter	clinical testing	This sequence change replaces tryptophan, which is neutral and slightly polar, with cysteine, which is neutral and slightly polar, at codon 291 of the NPC1 protein (p.Trp291Cys). This variant is present in population databases (rs138151007, gnomAD 0.1%). This variant has not been reported in the literature in individuals affected with NPC1-related conditions. ClinVar contains an entry for this variant (Variation ID: 289805). 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. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Fulgent Genetics, Fulgent Genetics	RCV000649022	SCV000896689	uncertain significance	Niemann-Pick disease, type C1	2022-04-14	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000649022	SCV001283585	uncertain significance	Niemann-Pick disease, type C1	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
PreventionGenetics, part of Exact Sciences	RCV003391055	SCV004111385	uncertain significance	NPC1-related condition	2023-05-01	criteria provided, single submitter	clinical testing	The NPC1 c.873G>T variant is predicted to result in the amino acid substitution p.Trp291Cys. This variant was observed in one individual in a cohort study of inborn errors of metabolism in psychiatric populations (Sriretnakumar et al. 2019. PubMed ID: 30556376). This variant in the heterozygous condition was reported in one individual with cholestatic disorder, however, the individual symptoms were resolved without intervention (Jeyaraj et al. 2021. PubMed ID: 34828443). This variant is reported in 0.12% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/18-21140203-C-A). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Mayo Clinic Laboratories, Mayo Clinic	RCV000675579	SCV000801270	uncertain significance	not provided	2017-05-17	no assertion criteria provided	clinical testing
Natera, Inc.	RCV000649022	SCV001455881	uncertain significance	Niemann-Pick disease, type C1	2020-09-16	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000675579	SCV001551024	uncertain significance	not provided		no assertion criteria provided	clinical testing	The NPC1 p.Trp291Cys variant was not identified in the literature but was identified in dbSNP (ID: rs138151007), ClinVar (classified as uncertain significance by EGL Genetics, Fulgent Genetics, Invitae, and Mayo Clinic), and LOVD 3.0 (variant effect not shared). The variant was identified in control databases in 32 of 281902 chromosomes at a frequency of 0.0001135 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: African in 31 of 24830 chromosomes (freq: 0.001248) and Latino in 1 of 35406 chromosomes (freq: 0.000028), but was not observed in the Ashkenazi Jewish, East Asian, European (Finnish), European (non-Finnish), Other, or South Asian populations. The p.Trp291 residue is conserved in mammals but not in more distantly related organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and two of four in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.