ClinVar Miner

Submissions for variant NM_152594.3(SPRED1):c.46C>T (p.Arg16Ter) (rs1057517941)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000414009 SCV000491135 pathogenic not provided 2016-09-19 criteria provided, single submitter clinical testing The R16X nonsense variant in the SPRED1 gene has been observed in multiple individuals with cafe au lait spots with or without freckling who had negative NF1 gene testing (Spencer et al., 2011; Pasmant et al., 2015; Stenson et al., 2014). This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The R16X variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations.
Invitae RCV000705365 SCV000834357 pathogenic Legius syndrome 2018-07-03 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg16*) in the SPRED1 gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been reported in several individuals affected with Legius syndrome (PMID: 19443465, 19366998, 25074460, 28150585). ClinVar contains an entry for this variant (Variation ID: 372718). Loss-of-function variants in SPRED1 are known to be pathogenic (PMID: 17704776). For these reasons, this variant has been classified as Pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000705365 SCV001339262 pathogenic Legius syndrome 2020-03-10 criteria provided, single submitter clinical testing Variant summary: SPRED1 c.46C>T (p.Arg16X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant was absent in 251148 control chromosomes (gnomAD). c.46C>T has been reported in the literature in individuals affected with Neurofibromatosis type 1-like Syndrome (Legius Syndrome) (e.g. Messiaen_2009, Pasmant_2009, Sekelska_2017, Spurlock_2009). These data indicate that the variant is likely to be associated with disease. Two ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

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