Submissions for variant NM_000271.5(NPC1):c.2861C>T (p.Ser954Leu)

gnomAD frequency: 0.00010  dbSNP: rs543206298

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000254670	SCV000208909	pathogenic	not provided	2022-08-01	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 21228398, 26338816, 26666848, 24676439, 32138288, 32071943, 25238906, 24915861, 10521290, 23773996, 25236789, 27544496, 28421028, 23433426, 31635081, 15465421, 32222928, 31980526, 34426522, 31589614, 33098801, 33624863)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000158972	SCV000770849	pathogenic	Niemann-Pick disease, type C1	2024-01-18	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 954 of the NPC1 protein (p.Ser954Leu). This variant is present in population databases (rs543206298, gnomAD 0.03%). This missense change has been observed in individual(s) with Niemann-Pick disease (PMID: 11182931, 12401890, 23773996, 24915861, 26666848, 27581084). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 181457). 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. For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV000158972	SCV000893486	pathogenic	Niemann-Pick disease, type C1	2018-10-31	criteria provided, single submitter	clinical testing
Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	RCV000158972	SCV001149856	pathogenic	Niemann-Pick disease, type C1	2018-10-23	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000254670	SCV001335074	pathogenic	not provided	2020-02-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001193400	SCV001362189	pathogenic	Niemann-Pick disease, type C	2019-07-09	criteria provided, single submitter	clinical testing	Variant summary: NPC1 c.2861C>T (p.Ser954Leu) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 7.6e-05 in 251102 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in NPC1 causing Niemann-Pick Disease Type C (7.6e-05 vs 0.0028), allowing no conclusion about variant significance. The variant, c.2861C>T, has been reported in the literature in multiple individuals affected with Niemann-Pick Disease Type C (e.g. Reunert_2016, Tarugi_2002). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three ClinVar submitters (evaluation after 2014) cite this variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000254670	SCV001446737	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000158972	SCV003824110	pathogenic	Niemann-Pick disease, type C1	2022-06-14	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003407592	SCV004114773	pathogenic	NPC1-related disorder	2023-09-04	criteria provided, single submitter	clinical testing	The NPC1 c.2861C>T variant is predicted to result in the amino acid substitution p.Ser954Leu. This variant has been reported, along with another NPC1 variant, in many individuals with Niemann-Pick type C disease (see examples: Greer et al. 1999. PubMed ID: 10521290; Bauer et al. 2013. PubMed ID: 23773996; Imrie et al. 2015. PubMed ID: 26666848; Dardis et al. 2020. PubMed ID: 32138288; Koens et al. 2016. PubMed ID: 27581084; Yamamoto et al. 2000. PubMed ID: 11182931; Zhang et al. 2014. PubMed ID: 24915861; Reunert et al. 2015. PubMed ID: 26981555). In vitro functional studies demonstrate that expression of this variant decelerates cholesterol clearance (Feng et al. 2019. PubMed ID: 31635081). This variant is reported in 0.032% of alleles in individuals of European (Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/18-21119369-G-A). This variant is interpreted as pathogenic.
Laboratory of Medical Genetics, National & Kapodistrian University of Athens	RCV000158972	SCV005051891	pathogenic	Niemann-Pick disease, type C1	2024-02-01	criteria provided, single submitter	curation
Counsyl	RCV000158972	SCV000220623	pathogenic	Niemann-Pick disease, type C1	2019-07-23	no assertion criteria provided	clinical testing
Natera, Inc.	RCV000158972	SCV001453838	pathogenic	Niemann-Pick disease, type C1	2020-09-16	no assertion criteria provided	clinical testing