Submissions for variant NM_000271.5(NPC1):c.852del (p.Phe284fs)

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Total submissions: 5

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Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000409772	SCV000486705	pathogenic	Niemann-Pick disease, type C1	2016-07-21	criteria provided, single submitter	clinical testing
Invitae	RCV000409772	SCV000832555	pathogenic	Niemann-Pick disease, type C1	2023-04-24	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 371187). This premature translational stop signal has been observed in individual(s) with Niemann-Pick type C disease (PMID: 19252935, 23142039). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Phe284Leufs*26) in the NPC1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in NPC1 are known to be pathogenic (PMID: 9211850).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001731664	SCV001983444	pathogenic	Niemann-Pick disease, type C	2021-09-04	criteria provided, single submitter	clinical testing	Variant summary: NPC1 c.852delT (p.Phe284LeufsX26) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 250484 control chromosomes. c.852delT has been reported in the literature in multiple individuals affected with Niemann-Pick Disease Type C (example, Fancello_2009, Rodrguez-Pascau_2012). 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. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
3billion	RCV000409772	SCV003842065	pathogenic	Niemann-Pick disease, type C1	2023-02-23	criteria provided, single submitter	clinical testing	The variant is not observed in the gnomAD v2.1.1 dataset. This variant was predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (PMID: 19252935 / 3billion dataset). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Natera, Inc.	RCV000409772	SCV002095220	pathogenic	Niemann-Pick disease, type C1	2021-05-04	no assertion criteria provided	clinical testing

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