ClinVar Miner

Submissions for variant NM_152594.3(SPRED1):c.796_797del (p.Met266fs) (rs864622410)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000204318 SCV000260510 pathogenic Legius syndrome 2019-04-01 criteria provided, single submitter clinical testing This sequence change deletes 2 nucleotides in exon 7 of the SPRED1 mRNA (c.796_797delAT), causing a frameshift at codon 266. This creates a premature translational stop signal in the last exon of the SPRED1 mRNA (p.Met266Valfs*4). While this is not anticipated to result in nonsense mediated decay, it is expected to result in a truncated SPRED1 protein with nearly 40% of residues lost. This variant is not present in population databases (ExAC no frequency). This variant has been reported in 3 individuals with cafe au lait macules who did not have any pathogenic variants in NF1 (PMID: 17704776, Invitae database). ClinVar contains an entry for this variant (Variation ID: 220172). Experimental studies have shown that this truncation results in loss of the ability to inhibit RAF-MEK-ERK signaling and in sub-cellular mislocalization of the SPRED1 protein (PMID: 17704776, 22751498). For these reasons, this variant has been classified as Pathogenic.
Center for Human Genetics, Inc,Center for Human Genetics, Inc RCV000204318 SCV000782325 pathogenic Legius syndrome 2016-11-01 criteria provided, single submitter clinical testing

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