ClinVar Miner

Submissions for variant NM_000271.5(NPC1):c.665A>G (p.Asn222Ser) (rs55680026)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 10
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics 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,PreventionGenetics RCV000254118 SCV000303389 likely benign not specified criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000078485 SCV000608853 uncertain significance not provided 2018-09-01 criteria provided, single submitter clinical testing
DNA and Cytogenetics Diagnostics Unit,Erasmus Medical Center RCV000509165 SCV000744749 likely benign Niemann-Pick disease type C1 2017-05-05 criteria provided, single submitter clinical testing
Invitae RCV000509165 SCV001012165 likely benign Niemann-Pick disease type C1 2019-12-31 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,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.
Integrated Genetics/Laboratory Corporation of America RCV000254118 SCV001362188 uncertain significance not specified 2019-05-03 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 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, 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 phenotype (0.0028), strongly 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). 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 - not known which one the variant was in cis with). 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 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). Five ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant with conflicting classifications: three times as likely benign and twice as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
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.
Genome Diagnostics Laboratory,VU University Medical Center Amsterdam RCV000509165 SCV000745717 likely benign Niemann-Pick disease type C1 2017-09-21 no assertion criteria provided clinical testing

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.