ClinVar Miner

Submissions for variant NM_000271.5(NPC1):c.3742_3745del (p.Leu1248fs) (rs774943545)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000576310 SCV000678022 likely pathogenic Niemann-Pick disease type C1 2014-01-02 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000589877 SCV000696421 pathogenic Niemann-Pick disease, type C 2017-07-03 criteria provided, single submitter clinical testing Variant summary: The NPC1 c.3742_3745delCTCA (p.Leu1248Valfs) variant (also known as 3741_3744delACTC) results in a premature termination codon, predicted to cause a truncated or absent NPC1 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. This variant was found in 5/121194 control chromosomes from ExAC at a frequency of 0.0000413, which does not exceed the estimated maximal expected allele frequency of a pathogenic NPC1 variant (0.0027735). The variant was detected in at least three patients with NPC. Variant downsteam of this variant c.3744_3747 delCAGT has also been reported in affected individual and listed as "DM-disease mutation" in HGMD, suggesitng this location is a mutation hotspot. Taken together, this variant is classified as pathogenic.
Invitae RCV000576310 SCV001213659 pathogenic Niemann-Pick disease type C1 2019-10-23 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the NPC1 gene (p.Leu1248Valfs*3). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 31 amino acids of the NPC1 protein. This variant is present in population databases (rs774943545, ExAC 0.006%). This variant has been observed in individuals affected with Niemann-Pick type C and to segregate with disease in one family (PMID: 10521290, 19744920). This variant is also known as c.3741_3744delACTC in the literature. ClinVar contains an entry for this variant (Variation ID: 487441). Experimental studies and prediction algorithms are not available for this variant, and the functional significance of the affected amino acid(s) is currently unknown. For these reasons, this variant has been classified as Pathogenic.

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