ClinVar Miner

Submissions for variant NM_152594.3(SPRED1):c.1196dup (p.Phe400fs) (rs1555392791)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000546970 SCV000645814 likely pathogenic Legius syndrome 2017-05-16 criteria provided, single submitter clinical testing This sequence change inserts 1 nucleotide in exon 7 of the SPRED1 mRNA (c.1196dupA), causing a frameshift at codon 400. This creates a premature translational stop signal in the last exon of the SPRED1 mRNA (p.Phe400Valfs*32). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 45 amino acids of the SPRED1 protein. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a SPRED1-related disease. Multiple downstream truncations have been reported in individuals affected with neurofibromatosis type 1-like syndrome (NFLS) (PMID: 19920235). This suggests that deletion of this region of the SPRED1 protein is causative of disease. While experimental studies have not been performed on this particular variant, it is expected to disrupt the Sprouty related domain of the SPRED1 protein which is necessary for proper function of the SPRED1 protein (PMID: 15683364). In summary, this variant is a novel truncation located in the last exon of SPRED1, upstream of truncations that have been reported in affected individuals, and located in a functionally important region of the protein. This evidence indicates that the variant is pathogenic, but additional data is needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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