ClinVar Miner

Submissions for variant NM_000271.5(NPC1):c.3517dup (p.Arg1173fs) (rs1555631982)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000556164 SCV000650847 pathogenic Niemann-Pick disease type C1 2019-03-20 criteria provided, single submitter clinical testing This sequence change inserts 1 nucleotide in exon 23 of the NPC1 mRNA (c.3517dupA), causing a frameshift at codon 1173. This creates a premature translational stop signal in the last exon of the NPC1 mRNA (p.Arg1173Lysfs*85). While this is not anticipated to result in nonsense mediated decay, it is expected to result in a truncated NPC1 protein. While this variant has not been reported in the literature, truncating variants in NPC1 are known to be pathogenic (PMID: 19252935, 23433426). Other variants downstream of this position producing similar frameshift and truncating effects have been observed in patients affected with NPC (PMID: 19252935), suggesting that the sequence integrity of the exons affected by this variant is essential for NPC1 function. In addition, this variant has been observed in the homozygous state in an affected individual with positive filipin staining, indicating functional deficiency of the NPC1 protein (Invitae). For these reasons, this variant has been classified as Pathogenic.

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