Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Eurofins Ntd Llc |
RCV000724988 | SCV000332999 | pathogenic | not provided | 2015-07-24 | criteria provided, single submitter | clinical testing | |
| Illumina Laboratory Services, |
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 | 2023-11-24 | 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. Loss-of-function variants in NPC1 are known to be pathogenic (PMID: 9211850). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with a NPC1-related condition (PMID: 29100954). ClinVar contains an entry for this variant (Variation ID: 281941). 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 |