Submissions for variant NM_000271.5(NPC1):c.2819C>T (p.Ser940Leu)

gnomAD frequency: 0.00001  dbSNP: rs143124972

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000728524	SCV000856111	pathogenic	not provided	2017-08-18	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000781669	SCV000919892	pathogenic	Niemann-Pick disease, type C	2017-12-29	criteria provided, single submitter	clinical testing	Variant summary: The NPC1 c.2819C>T (p.Ser940Leu) variant involves the alteration of a conserved nucleotide and 5/5 in silico tools predict a damaging outcome for this variant. This variant was found in 3/244918 control chromosomes (gnomAD) at a frequency of 0.0000122, which does not exceed the estimated maximal expected allele frequency of a pathogenic NPC1 variant (0.0027735). Multiple publications have cited the variant in affected homozygote and compound heterozygote individuals. In addition, a clinical diagnostic laboratory classified this variant as likely pathogenic. Taken together, this variant is classified as pathogenic.
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000169010	SCV001369023	pathogenic	Niemann-Pick disease, type C1	2019-10-22	criteria provided, single submitter	clinical testing	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PM2,PM3,PP3,PP5.
Myriad Genetics, Inc.	RCV000169010	SCV002060174	pathogenic	Niemann-Pick disease, type C1	2021-11-11	criteria provided, single submitter	clinical testing	NM_000271.4(NPC1):c.2819C>T(S940L) is a missense variant classified as pathogenic in the context of Niemann-Pick disease type C1. S940L has been observed in cases with relevant disease (PMID: 26981555, 11349231, 25425405, 21245028, 16126423, 23146215, 16720792, 30285904, 26790753). Functional assessments of this variant are not available in the literature. S940L has been observed in population frequency databases (gnomAD: AFR 0.01%). In summary, NM_000271.4(NPC1):c.2819C>T(S940L) is a missense variant that has been observed more frequently in cases with the relevant disease than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000169010	SCV002175947	pathogenic	Niemann-Pick disease, type C1	2024-12-10	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 940 of the NPC1 protein (p.Ser940Leu). This variant is present in population databases (rs143124972, gnomAD 0.003%). This missense change has been observed in individual(s) with Niemann-Pick disease type C (PMID: 26790753, 28105569, 28710748, 32138288). ClinVar contains an entry for this variant (Variation ID: 188716). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt NPC1 protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.
Mayo Clinic Laboratories, Mayo Clinic	RCV000728524	SCV004226692	likely pathogenic	not provided	2022-05-03	criteria provided, single submitter	clinical testing	PP1, PP3, PM2, PM3_very_strong
Natera, Inc.	RCV000169010	SCV001453841	pathogenic	Niemann-Pick disease, type C1	2020-09-16	no assertion criteria provided	clinical testing