Submissions for variant NM_000271.5(NPC1):c.665A>G (p.Asn222Ser)

gnomAD frequency: 0.00329  dbSNP: rs55680026

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000254118	SCV000110341	likely benign	not specified	2015-09-22	criteria provided, single submitter	clinical testing
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000078485	SCV000281602	uncertain significance	not provided	2015-06-04	criteria provided, single submitter	clinical testing	Converted during submission to Uncertain significance.
PreventionGenetics, part of Exact Sciences	RCV003891533	SCV000303389	likely benign	NPC1-related disorder	2019-05-24	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
CeGaT Center for Human Genetics Tuebingen	RCV000078485	SCV000608853	uncertain significance	not provided	2024-04-01	criteria provided, single submitter	clinical testing
Invitae	RCV000509165	SCV001012165	likely benign	Niemann-Pick disease, type C1	2024-02-01	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000509165	SCV001283587	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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000254118	SCV001362188	likely benign	not specified	2023-07-21	criteria provided, single submitter	clinical testing	Variant summary: NPC1 c.665A>G (p.Asn222Ser) results in a conservative amino acid change located in the Niemann-Pick C1, N-terminal domain (IPR032190) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0034 in 250650 control chromosomes (gnomAD), predominantly at a frequency of 0.0051 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 2 fold of the estimated maximal expected allele frequency for a pathogenic variant in NPC1 causing Niemann-Pick Disease Type C (0.0027), suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin.c.665A>G has been reported in the literature in multiple individuals presenting with varying phenotypes from Niemann-Pick Disease Type C, late-onset/adult and late infantile forms, familial epileptogenic encephalopathy with a peculiar form of degenerative glial tauopathy, neonatal cholestasis, epilepsy and psycotic symptoms, splenomegaly, and low and high HDL-C (Cupidi_2018, DeCastro-Oros_2017, Fancello_2009, Imrie_2007, Park_2003, Romanello_2016, Sadananda_2015, Stampfer_2013, Wassif_2016, Dardis_2020, Touma_2020 and Lopez de Fruto_2021). The variant has presented in isolation (no second NPC1 allele identified), as a compound heterozygote with another pathogenic NPC1 variant (I1061T, P1007A) and in co-occurrence with two additional pathogenic NPC1 variants (I1061T/R958Q - phase is not known). The variant was also detected in homozygous state in one young obese patient without other phenotypic information provided (Liu_2017). These reports do not provide unequivocal conclusions about association of the variant with Niemann-Pick Disease Type C. Experimental evidence evaluating an impact on protein function demonstrated that the variant protein was secreted and showed normal behavior and cellular localization, while protein expression and cholesterol transporting ability were similar to wild type (Liu_2017, Infante_2008). The following publications have been ascertained in the context of this evaluation (PMID: 32138288, 28222799, 30153451, 19252935, 17160617, 17989072, 28130309, 32745579, 12955717, 26790753, 26255038, 23433426, 33990640, 25764212). Nine ClinVar submitters have assessed the variant since 2014: four classified the variant as uncertain significance, four as likely benign, and one as benign. Based on the evidence outlined above, the variant was classified as likely benign.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000078485	SCV001474282	benign	not provided	2020-01-06	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000509165	SCV001652769	uncertain significance	Niemann-Pick disease, type C1	2021-05-18	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002514379	SCV003695621	likely benign	Inborn genetic diseases	2021-06-25	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Mayo Clinic Laboratories, Mayo Clinic	RCV000078485	SCV004224468	uncertain significance	not provided	2023-02-24	criteria provided, single submitter	clinical testing	BS1
GenomeConnect, ClinGen	RCV000509165	SCV000607048	not provided	Niemann-Pick disease, type C1		no assertion provided	phenotyping only	GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.
Natera, Inc.	RCV000509165	SCV001463712	likely benign	Niemann-Pick disease, type C1	2019-12-30	no assertion criteria provided	clinical testing