ClinVar Miner

Submissions for variant NM_000271.5(NPC1):c.1554-1009G>A

dbSNP: rs1055204017
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000669325 SCV000794069 likely pathogenic Niemann-Pick disease, type C1 2017-09-13 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV000669325 SCV000893489 pathogenic Niemann-Pick disease, type C1 2018-10-31 criteria provided, single submitter clinical testing
Invitae RCV000669325 SCV001228470 pathogenic Niemann-Pick disease, type C1 2023-11-28 criteria provided, single submitter clinical testing This sequence change falls in intron 9 of the NPC1 gene. It does not directly change the encoded amino acid sequence of the NPC1 protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with biochemical and clinical features of Niemann-Pick type C disease (PMID: 20718790, 23593294, 25425405, 28480683, 29453517). This variant is also known as IVS9–1009G>A. ClinVar contains an entry for this variant (Variation ID: 553804). Studies have shown that this variant results in inclusion of a pseudoexon and introduces a premature termination codon (PMID: 19718781, 28167839). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.
PreventionGenetics, part of Exact Sciences RCV003420185 SCV004109249 pathogenic NPC1-related condition 2023-08-25 criteria provided, single submitter clinical testing The NPC1 c.1554-1009G>A variant is predicted to interfere with splicing. This variant occurs within a deep intronic region and has been reported in the compound heterozygous state in patients with Niemann-Pick disease type C1 (Rodríguez-Pascau et al. 2009. PubMed ID: 19718781; Patients SEQ1 and 2 in Hastings et al. 2019. PubMed ID: 31639011; Zeiger et al. 2018. PubMed ID: 29453517). A functional study has shown that the c.1554-1009G>A variant promotes a pseudoexon insertion and interferes with normal splicing (Rodríguez-Pascau et al. 2009. PubMed ID: 19718781). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. In ClinVar, this variant has been interpreted as pathogenic or likely pathogenic by multiple laboratories (https://www.ncbi.nlm.nih.gov/clinvar/variation/553804/). This variant is interpreted as pathogenic.
Natera, Inc. RCV000669325 SCV002095201 pathogenic Niemann-Pick disease, type C1 2021-04-26 no assertion criteria provided clinical testing

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