ClinVar Miner

Submissions for variant NM_152594.3(SPRED1):c.1A>G (p.Met1Val)

dbSNP: rs1894017295
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Centre for Mendelian Genomics, University Medical Centre Ljubljana RCV001196448 SCV001367056 pathogenic Legius syndrome 2019-09-12 criteria provided, single submitter clinical testing This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PM2,PP4.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV001196448 SCV004848090 likely pathogenic Legius syndrome 2017-07-24 criteria provided, single submitter clinical testing The p.Met1? (c.1A>G) variant in SPRED1 has not been previously reported in individuals with clinical features of a RASopathy and was absent from large population studies. However, another variant at this codon (c.2T>C, p.Met1?) has been reported in 1 individual with neurofibromatosis-like syndrome and segregated with disease in 3 affected relatives (Pasmant 2009). The c.2T>C variant results in an novel initiation codon 22 amino acids downstream, which was transcribed into RNA with 21 amino acids lost from the EVH-1 functional domain (Pasmant 2009). If translated, this RNA would be expected to result in a nonfunctional protein (Pasmant 2009) as the EVH-1 functional domain is required for the suppression of ERK (Brems 2007). In summary, although additional studies are required to fully establish its clinical significance, the p.Met1? (c.1A>G) variant is likely pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp RCV001196448 SCV005702872 pathogenic Legius syndrome 2024-07-11 criteria provided, single submitter clinical testing This sequence change affects the initiator methionine of the SPRED1 mRNA. The next in-frame methionine is located at codon 22. This variant is not present in population databases (gnomAD no frequency). Disruption of the initiator codon has been observed in individuals with clinical features of Legius syndrome (PMID: 19366998, 32107864; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 930640). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. For these reasons, this variant has been classified as Pathogenic.

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