ClinVar Miner

Submissions for variant NM_152594.3(SPRED1):c.973C>T (p.Arg325Ter) (rs1057518683)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000415388 SCV000823235 pathogenic Legius syndrome 2018-10-24 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the SPRED1 gene (p.Arg325*). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 120 amino acids of the SPRED1 protein. This variant is not present in population databases (ExAC no frequency). This variant has been observed in an individual with Legius syndrome (PMID: 17704776), and has also been observed to segregate with Legius syndrome in a family (PMID: 25883013). This variant was also observed to be de novo in an individual, but that individual was also homozygous for a different pathogenic variant (PMID: 27959697). ClinVar contains an entry for this variant (Variation ID: 374301). Experimental studies have shown that this nonsense change results in a lost ability to inhibit Raf-MEK-ERK signaling in vitro (PMID: 17704776). This variant disrupts the C-terminus of the SPRED1 protein. Other variant(s) that disrupt this region (p.Arg349Glyfs*11 and p.Gly385Ilefs*20) have been determined to be pathogenic (PMID: 21089071, 21649642, 17704776). This suggests that variants that disrupt this region of the protein are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics RCV000415388 SCV000328775 pathogenic Legius syndrome 2015-04-10 no assertion criteria provided clinical testing This de novo pathogenic variant has been previously reported as disease-causing [PMID 17704776] and was found in our laboratory in a 6 month old female with delayed motor milestones, generalized hypotonia with tracheostomy, micrognathia, camptodactyly and overriding toes, failure to thrive, patent foramen ovale, and hemangioma on the left hand. A homozygous pathogenic variant in MEGF10 (NM_032446.2, c.1557delA) was reported in the same individual.

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