ClinVar Miner

Submissions for variant NM_000271.5(NPC1):c.1920del (p.His641fs) (rs886042270)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000724988 SCV000332999 pathogenic not provided 2015-07-24 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000380677 SCV000915801 likely pathogenic Niemann-Pick disease type C1 2018-12-06 criteria provided, single submitter clinical testing The NPC1 c.1920delG (p.His641ThrfsTer2) variant results in a frameshift, and is predicted to result in premature termination of the protein. The p.His641ThrfsTer2 variant has been reported in two studies in which it is identified in a compound heterozygous state with either a missense variant or a second frameshift variant in three individuals (including a pair of twins) with Niemann-Pick disease type C (NPC) (Megias-Vericat et al. 2017; Lipinski et al. 2018). Control data are unavailable for this variant and it is not found in the 1000 Genomes Project, the Exome Sequencing Project, Exome Aggregation Consortium, or the Genome Aggregation Database in a region of good sequence coverage so it is presumed rare. The variant is noted to be located in the SSD domain, which is important for cholesterol binding. A mouse model generated with the p.His641ThrfsTer2 variant in a compound heterozygosity was noted to recapitulate the hallmarks of NPC (Gomez-Grau et al. 2017). Based on the collective evidence and potential impact of frameshift variants, the p.His641ThrfsTer2 variant is classified as likely pathogenic for Niemann-Pick disease type C. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Invitae RCV000380677 SCV000940380 pathogenic Niemann-Pick disease type C1 2018-08-10 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.His641Thrfs*2) in the NPC1 gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been observed in an individual affected with a NPC1-related condition (PMID: 29100954). ClinVar contains an entry for this variant (Variation ID: 281941). Loss-of-function variants in NPC1 are known to be pathogenic (PMID: 9211850). For these reasons, this variant has been classified as Pathogenic.
Counsyl RCV000380677 SCV000485355 likely pathogenic Niemann-Pick disease type C1 2015-11-24 no assertion criteria provided clinical testing

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